Reproductive Biology and
Endocrinology
BioMed Central
Open Access
Review
Potential biological role of poly (ADP-ribose) polymerase (PARP) in
male gametes
Ashok Agarwal*1, Reda Z Mahfouz1, Rakesh K Sharma1, Oli Sarkar2,3,
Devna Mangrola1 and Premendu P Mathur2
Address: 1Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA, 2Department of Biochemistry and Molecular Biology,
Pondicherry University, Pondicherry, India and 3McGill University Health Center, Montreal, Canada
Email: Ashok Agarwal* - agarwaa@ccf.org; Reda Z Mahfouz - mahfour@ccf.org; Rakesh K Sharma - sharmar@ccf.org;
Oli Sarkar - olisarkar@yahoo.com; Devna Mangrola - deanmangrola@yahoo.com; Premendu P Mathur - ppmathur@rediffmail.com
* Corresponding author
Published: 5 December 2009
Reproductive Biology and Endocrinology 2009, 7:143
doi:10.1186/1477-7827-7-143
Received: 24 June 2009
Accepted: 5 December 2009
This article is available from: http://www.rbej.com/content/7/1/143
© 2009 Agarwal et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Maintaining the integrity of sperm DNA is vital to reproduction and male fertility. Sperm contain a
number of molecules and pathways for the repair of base excision, base mismatches and DNA
strand breaks. The presence of Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, and
its homologues has recently been shown in male germ cells, specifically during stage VII of
spermatogenesis. High PARP expression has been reported in mature spermatozoa and in proven
fertile men. Whenever there are strand breaks in sperm DNA due to oxidative stress, chromatin
remodeling or cell death, PARP is activated. However, the cleavage of PARP by caspase-3
inactivates it and inhibits PARP's DNA-repairing abilities. Therefore, cleaved PARP (cPARP) may be
considered a marker of apoptosis. The presence of higher levels of cPARP in sperm of infertile men
adds a new proof for the correlation between apoptosis and male infertility. This review describes
the possible biological significance of PARP in mammalian cells with the focus on male reproduction.
The review elaborates on the role played by PARP during spermatogenesis, sperm maturation in
ejaculated spermatozoa and the potential role of PARP as new marker of sperm damage. PARP
could provide new strategies to preserve fertility in cancer patients subjected to genotoxic stresses
and may be a key to better male reproductive health.
Background
Male fertility is affected by a variety of environmental,
behavioral, and genetic factors that can alter spermatogenesis at various levels [1-3]. Male germ cells are exposed to
a wide variety of endogenous and exogenous genotoxic
agents. Endogenous agents include reactive oxygen and
nitrogen species generated during the metabolic activities
of cells [4,5]. Exogenous agents include various environmental factors that can inflict damage to genomic DNA.
These genotoxic agents can introduce DNA lesions in the
form of DNA single and double strand breaks, abasic sites,
base damage, inter-and intra-strand cross links and DNAprotein cross links [6,7]. Origin of DNA damage in
human spermatozoa can occur by abortive apoptosis,
abnormal chromatin packaging, generation of reactive
oxygen species and premature release from Sertoli cells [812].
During spermatogenesis, germ cell DNA in the nucleus is
nicked by topoisomerases in order to relieve the torsional
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stress created when DNA is compacted into the differentiating sperm head. Persistence of DNA strand breaks during different stages of spermatogenesis contribute to DNA
damage detected in mature spermatozoa [13,14]. As spermatids are haploid, they must resolve double stranded
DNA breaks by an error-prone DNA repair mechanism
[15]. Interest in male germ cell DNA quality has increased
in recent decades especially in the era of assisted reproductive technologies (ART). As natural selection of spermatozoa for fertilization is bypassed in procedures such as
intracytoplasmic sperm injection (ICSI), awareness has
been raised regarding the possibility of congenital anomalies. Many reviews have dealt with the origin of sperm
DNA integrity, evaluation of available technologies to
assess sperm DNA integrity and its impact on the outcome
of ART [16-24]. Environmental, life style and occupational hazards in male infertility have also been extensively studied [25-33]. These factors may affect DNA
repair pathways and impact male fertility and subsequent
embryo development.
polymerization from donor NAD+ molecules into target
proteins. PARP1 is the prototype and most abundantly
expressed member of a family of PARPs.
In this review we will discuss the role of Poly (ADPribose) polymerase (PARP), a DNA damage repair proteins and highlight its role in ejaculated human spermatozoa. Recently the focus of PARP's role in malignancy has
intensified to include use of PARP inhibition as an adjuvant therapy with chemotherapeutic drugs [34]. As our
interest lies primarily in male reproductive health, in this
review we will focus on the biological role of PARP in general as well as in male gamete and highlight possible role
of PARP in modulating DNA damage in male germ cells.
PARP family members can be divided into several subcategories or groups based on each protein's established
functional domains and precise functions into: 1) DNA
dependent PARPs (PARP1 and PARP2) that are activated
by DNA strand breaks 2) Tankyrases (tankyrase-1 and
tankyrase-2) that serve diverse functions such as telomere
regulation and mitotic segregation 3) CCCH-type PARPs
(PARP12, PARP13) which contain special CCCH type zinc
fingers and 4) PARP9, PARP14, and PARP15 consisting of
macro PARP's which have 1-3 macrodomains connected
to a PARP domain. They also have WWE domain and
PARP catalytic activity. PARP6, 8, 11 and 16 do not have
any recognized domains or functions and therefore they
have not been assigned proper nomenclature [56].
Poly (ADP-ribose) polymerase (PARP)
Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme
has a particularly well-researched role in base excision
repair; it is one of the primary repair mechanisms to
resolve DNA lesions caused by endogenous processes as
well as those caused by exogenous chemical exposure and
irradiation [35,36]. PARP also has a well-documented role
in testicular germ cells [37-39], including a role in DNA
damage repair of germ cells [40]. However, a similar role
for PARP in human ejaculated spermatozoa is still being
investigated. The last decade has seen increasing interest
in the relationship between DNA integrity in mature ejaculated spermatozoa and male infertility [16,26,41-43].
Focus on genomic integrity of the male gametes has been
further intensified by the growing concern about the
transmission of genetic diseases through intracytoplasmic
sperm injection (ICSI) [44-49].
Proteins involved in the major repair pathways have been
shown to be expressed in the testis [50]. PARP proteins are
involved in detection of strand breaks and signaling in
both the base excision repair and nucleotide repair pathways [51,52]. PARP catalyzes poly (ADP-ribose) (PAR)
The PARP family consists of 18 homologues (PARP 1-18)
with a conserved catalytic domain made up of 50 amino
acid residues that serve as the 'PARP signature' [53]. This
is the site where poly(ADP-ribose) (PAR) chains are initiated, elongated, and where branching of the chains can
occur [54]. Besides this catalytic domain, PARP family
members may also have other domains including DNA
binding domains, macro-domains, breast cancer-1
(BRCA-1) C-Terminus (C-T) domain, ankyrin repeats and
a domain associated with protein-protein interaction
called WWE. BRCA-1 C-T domains are characteristic of
proteins responding to DNA damage at cell cycle checkpoints while WWE domains are found in proteins associated with ubiquitination. All of these special types of
domains contribute to the unique functions of each family member [53,55,56].
Recent classification system by Hassa and Hottiger groups
PARPs on the basis of their catalytic domain sequences
[54]. PARP family is divided into 3 separate groups: 1)
PARP1, PARPb (short PARP1), PARP2, and PARP3, 2)
PARP4 and 3) 2 PARP members, Tankyrase-1, tankyrase2a, and its isoform tankyrase-2b (also known as PARP5
and PARP6a/b) [54]. The various PARP enzymes can also
have different subcellular localization patterns. PARP1
and 2 are considered nuclear enzymes and are found in
the nucleus of cells. In contrast, tankyrases and PARP3 are
found in both the nucleus and cytoplasm [54,57].
Perhaps the best studied member of the PARP family is
PARP1, a 113 kD enzyme encoded by the ADP-ribosyl
transferase (ADPRT) gene in humans located on chromosome 1 [58,59]. PARP1 has been reported to be involved
in regulation of chromatin structure and transcription
processes in response to specific signaling pathways [55].
The protein structure of PARP1 is well characterized. Fig-
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Reproductive Biology and Endocrinology 2009, 7:143
ure 1 represents the PARP1 structure domains with clarification on the sites of the zinc fingers, PAR acceptance, and
cleavage site with short and long cleaved PARP1 fragments. PARP1 is made up of 3 functional domains including DNA binding domain (DBD), automodification
domain (AMD) and catalytic domains (CD). The DNA
binding domain contains zinc fingers that can bind to
breaks in DNA and contains the nuclear localization signal (NLS), which ensures the translocation of PARP1 into
the nucleus and also forms a site of cleavage by caspase 3.
The AMD is responsible for addition of ADP-ribose polymers to PARP1 itself. The catalytic domain is responsible
for the PARP activity [60] (Figure 1).
The DNA binding domain extends from the initiator
methionine (M) to threonine (T) 373 in human PARP1,
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and contains 2 well known structurally and functionally
unique zinc fingers (FI: amino acid 11-89; FII: amino
acids 115-199) [61,62]. A recently discovered third and
thus far an unrecognized zinc-binding motif, (FIII: amino
acid 233-373) has been reported [63,64]. DNA binding
domain contains a bipartite nuclear localization signal
(NLS) of the lysine (K) rich form KRK-X-KKKSKK (amino
acid 207-226) that targets PARP1 to the nucleus [65]. Zinc
fingers FI and FII are thought to recognize altered structures in DNA rather than particular sequences. These zinc
fingers have been reported to be involved in protein - protein interactions [66]. PARP1 strongly associates with single and double strand DNA breaks generated either
directly by DNA damage or indirectly by the enzymatic
excision of damaged bases during DNA repair processes.
Figure 1 domians of PARP and its fragments showing
Structural
Structural domains of PARP and its fragments showing. A: DNA binding domain containing Zinc fingers (F1-F3) for
nucleosome binding and nuclear localization (NLS) segment; Automodification domain responsible for adding ADPR (ADP
ribose) polymers through binding with Lysine (K) amino acid and catalytic domain has the PARP signature and PARP enzymatic
activity. B: Full length PARP1 113 KDa molecule with a mark on the site of cleavage (214/215 amino acids) C: PARP cleavage by
caspase showing short (24 KDa) and long (89 KDa) cleaved PARP fragments.
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Several studies suggest that the first zinc finger is required
for PARP1 activation by both DNA single and double
strand breaks, whereas the second zinc finger may exclusively act as a DNA single strand break sensor [61,62,67].
Additional studies are necessary for further identification
of interactions/localization of PARP or different mutation/polymorphisms of PARP in the pathophysiology of
oxidative stress, apoptosis and malignancies [68].
The major PAR acceptor protein is PARP1 itself, which
appears to accumulate roughly 90% of cellular PAR via
PARylation of its auto-modification domain. NAD is the
substrate of PARP enzymes that becomes cleaved forming
ADP-ribose and nicotinamide (Figure 2). Binding of mon-
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omer of ADP-ribose with PARP1 is mainly through hydrogen bonds on the c-terminus mainly the automodification
domain [53]. Interestingly, Altmeyer et al (2009) showed
that glutamic acid residue in the automodification
domain of PARP1 is not required for PAR formation.
Instead they identified lysine residues to be the PAR acceptor sites in PARP1 [67].
Role of PARP in metabolic pathways
The real challenge and the difficulty in understanding
PARP interaction and PAR metabolism is the lack of structural information that can be provided by X-ray crystallography or by nuclear magnetic resonance (NMR). Prior to
the recent findings by Altmeyer et al [67], the intense
Figureinteractions
PARP
2
in DNA damage/repair showing
PARP interactions in DNA damage/repair showing. A: DNA damage caused by genotoxic agents activates PARP with
HSP70 (heat shock protein 70) providing further activation B: activation of PAR formation with further help from other DNA
repair proteins such as XCCR1 (X-ray repair complementing defective repair in Chinese hamster ovary cells) that help DNA
polymerase to start sealing the damaged DNA strand C: DNA polymerase and ligase seal the DNA nicks releasing PARP and
other DNA binding proteins and D: repaired DNA.
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research on PARP was unable to confirm the presence of
glutamic acid residue in the AMD that may be functioning
as the PAR acceptor of amino acid in PARP1 [69]. This was
mainly due to the lack of mutational studies for PARP.
Figure 2 explains the possible PARP interaction with the
main proteins involved in DNA repair during DNA damage/repair process. The primary catalytic function of PARP
enzymes is to transfer ADP-ribose groups to the glutamate, aspartate and carboxy-terminal lysine residues of
proteins. With NAD serving as a cofactor, PAR polymerization begins by breaking the glycosidic bond between
ADP-ribose and nicontinamide. PARP can elongate the
amino acid chains of recipient proteins in a linear or
branched manner by the addition of up to 200 ADPribose groups [70].
PARP attaches ADP-ribose groups to a variety of protein
substrates. Perhaps the most common target of (ADPribosyl)ation is PARP1 itself, termed auto-modification
[71]. PARP enzymes commonly modify nucleosome proteins in order to restructure chromatin. While both histone H1 and H2B are acceptors of poly ADP-ribose,
histone H1 is the major acceptor recipient [72,73]. Histone H1t, a major H1 variant in testis, is the main H1 target of PARP during spermatogenesis [74]. PARP activity is
not restricted to nuclesome proteins; the well-known
tumor suppressor protein p53 is also modified by PARP1.
This modification transcriptionally inactivates p53 [75].
DNA polymerases modified by PARP have also been
inhibited during in vitro studies [76]. Toposiomerase II
can also be modified by PARP activity [77]. Similarly, the
transcription nuclear factor kappa β (NF-kβ) can also be
modified by ADP-ribose group attachment [78].
Regulation of PARP activity is important for exploring the
therapeutic options of this enzyme. Several types of molecules have been identified as activators of PARP activity
including histones, a common target of PARP. Though
histones H1 and H2B are modified by PARP1, histones
H1 and H3 reciprocally activate PARP1 [79,80]. Apart
from ribosylation, the structure of histones is regulated by
acetylation and silent information regulator gene (SIRT1),
a histone deacetylase, involved in the maintenance of histone structure. SIRT1 has a regulatory action on PARP1
activity and in the absence of SIRT-1, PARP remains
unregulated resulting in apoptosis inducing factor (AIF)
regulated cell death [81]. PARP activity is also activated by
a number of metal ions (like magnesium and calcium)
and polyamines. Incidentally, calcium ions also play an
important role in the pathophysiology associated with
oxidative stress and could provide a link to explain the
effect of oxidative stress on PARP activity [82-86].
There are a number of inhibitors used to study PARP activity such as endogenous purines (hypoxanthine and inos-
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ine) or exogenous molecules like caffeine derivatives or
tetracycline derivatives [80,87]. PARP1 phosphorylation
by ERK1/2 is required for maximal PARP1 activation after
DNA damage [88]. Furthermore DNA-dependent protein
kinase (DNA-PK), a protein involved in the repair of double strand breaks results in suppression of PARP activity
probably through direct binding and/or sequestration of
DNA-ends which serve as an important stimulator for
both DNA-PK and PARP [89].
PARP in mammalian cells
The most important role of PARP is its capacity to repair
DNA, especially in resolving single strand breaks. PARP1
and PARP2 have been shown to function in the repair of
base excision [60]. Additionally, PARP1 may play a role in
an alternate version of double strand DNA break repair
involving the DNA repair protein XRCC1 (X-ray repair
complementing defective repair in Chinese hamster ovary
cells 1) along with Ligase III and DNA-dependent protein
kinase involved in resealing DNA breaks [90,91]. PARP
interactions and it's role in the DNA repair process is
explained in Figure 2. PARP1/PARP2 get activated with
DNA breaks and interact along with other main DNA
repair proteins (XRCC1, DNA polymerase, DNA ligase III,
and other DNA binding proteins to repair the damaged
DNA strand. Heat shock protein may provide additional
activation for the PAR formation early in the DNA repair
[92] (Figure 2).
PARP1 binds to broken strands of DNA and automodifies
itself. It then dissociates from the single DNA strand due
to the negative charge it acquires from the ADP-ribose
group. After dissociating, PARP associates with DNA
Ligase III alpha, which is involved in the resealing of DNA
breaks, and XRCC1. XRCC1 then recruits other repair factors (such as DNA polymerase β, apurinic-apyrimidinic
(AP) endonuclease, and polynucleotide kinase) to complete the repair process [93]. Thus, PARP1 is part of an
important signaling pathway for DNA damage repair due
to its ability to recruit other repair enzymes necessary to
preserve DNA integrity of a cell. The role of PARP1 in base
excision repair (BER) was recognized by its interaction
with DNA polymerase β and its interaction with DNA
Ligase III and XRCC1. It was also shown that PARP1 deficient cells demonstrated significantly inhibited BER activity [94].
Similarly, PARP2 has also been shown to participate in
BER pathways, associating with DNA polymerase β,
XRCC1, and DNA Ligase III [51]. PARP2 deficient mice
showed significant delays in resealing single strand DNA
breaks similar to those seen in PARP1 deficient mice. This
is interesting because PARP2 activity is 10 times less than
that of PARP1. PARP1 and PARP2 also appear to
homodimerize and heterodimerize as a part of DNA
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Reproductive Biology and Endocrinology 2009, 7:143
repair [51]. PARP not only serves as part of a signaling
pathway in DNA damage repair but it is also involved in
the repair process. In particular, the binding of PARP1 to
the broken ends of DNA may protect it from degradation
by nucleases [95]. NBS1 (Nijmegen Breakage Syndrome
1) has been recently reported to be required for base excision repair (BER) [96].
A model put forth recently suggests that the involvement
of PARP in DNA damage repair is regulated by a feedback
mechanism [97]. PARP1 is first recruited to the DNA
break site and then binds to this site through its DNA
binding domain. The addition of PAR units enables the
recruitment of more PARP1 moieties through the AMD of
PARP1. The aggregation of PARP molecules then creates a
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signal that recruits other repair factors and forms the positive feedback mechanism of PARP. Interestingly, PARP
activity is subject to a negative feedback mechanism that
prevents excessive accumulation of poly (ADP-ribose)
and cell death [98,99].
PARP in cell cycle and cell death
In addition to being involved in the rescuing function of
DNA repair, PARP1 is also directly involved [100] in both
programmed cell death as well as necrosis [101-103] (Figure 3). PARP is part of the caspase-dependent pathway of
apoptosis and as part of this caspase mediating pathway;
PARP1 is cleaved by Caspase-3 into a 25 kDa N-terminal
and an 85 kDa C-terminal fragment. The 25 kDa fragment
consists of the DBD and the 85 kDa fragment consists of
Figure 3role of PARP in cell death in the event of DNA damage caused by ROS or a genotoxin, PARP targets the damaged site
Possible
Possible role of PARP in cell death in the event of DNA damage caused by ROS or a genotoxin, PARP targets
the damaged site. If high damage occurs, PARP may become overactivated resulting in ATP/NAD depletion and necrosis.
Apoptosis can also occur through caspase-3 activation and PARP cleavage. If low damage occurs, PARP can recruit other repair
enzymes and DNA repair can occur. Recently PARP1 dependent cell death termed as parthanatos has been reported, and is
distinct from apoptosis, necrosis or autophagy. Each arrow represents one or more reaction(s).
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the AMD and CD (Figure 1). The detachment of the DNAbinding domain from the automodification and catalytic
domains inactivates PARP1 and allows apoptosis to occur
[104]. Meanwhile, the N-terminal fragment inhibits any
uncleaved PARP1 molecules that are still present. Thus,
PARP1 cleavage effectively inhibits PARP activity that
could result in energy depletion as a result of consumption of a significantly large number of Nicotinamide adenine dinucleotide (NAD) molecules and lack of
ribosylation [105]. PARP1 is also involved in a caspaseindependent cell death pathway. When PARP1 is activated
by exposing fibroblast cultures to hydrogen peroxideinduced damage, it triggers caspase-independent pathway. PARP activation triggers the release of AIF from the
mitochondria and causes it to relocate to the nucleus
resulting in chromatinolyis [55,106-108].
PARP is also involved in a less organized version of cell
death-necrosis. Originally Berger et al proposed that
depletion of NAD caused an over-activation of PARP and
in the milieu of excessive DNA damage can cause necrosis
[109]. Heeres and Hergenrother proposed that over-accumulation of poly (ADP-ribose) are cytotoxic to cells and
induce them to undergo necrosis.
Thus PARP appears to be a two-sided coin. It has the
potential to respond to threats to DNA integrity, but its
over-activation can lead to cell death [101]. Figure 3 represent a schematic pathways that link the reactive oxygen
species (ROS) and genotoxins induced DNA damage with
the ATP/NAD levels that may determine the cell death
pathway depending upon the extent of the DNA damage,
caspase activation, and ATP/NAD levels. Modification of
PARP activity through inhibition or cleavage may lead to
apoptosis by preventing DNA repair provided by PARP.
However, recent report indicate that PARP may lead to
PARP1 dependent cell death that is reported to be distinct
from apoptosis, necrosis or autophagy and it is called
parthanatos [110].
The role of PARP in maintaining genomic integrity could
have profound implications for cell division. PARP is
associated with specific structures important for cell division such as centromeres and centrosomes, pointing to its
possible role in cell division. PARP1 associates with centrosomes during cell division and interphase, which may
be related to PARP1's role in maintaining chromosome
stability [111]. PARP1 is also involved in spindle structures necessary for cell division. Poly (ADP-ribosyl)ation
of spindle structures is essential for normal functioning
and assembly of spindles that if disturbed could result in
defective chromosome segregation [112,113]. PARP3 also
demonstrated an interaction with PARP1 at centrosomes
[57]. PARPs localize to active mammalian centromeres
primarily during metaphase and prometaphase
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[114,115]. PARP1 and PARP2 bind to the same centromere proteins, including the important mitotic checkpoint protein and Bub3 (budding uninhibited by
benzimidazoles 3) [55].
Chromatin remodeling and transcription
Poly (ADP-ribosyl)ation can be considered an epigenetic
modification [116] because its modification of histones
can remodel chromatin structure in order to provide
unique information for other proteins involved in not
only DNA repair but also in transcription [55,97]. The
role of PARP in transcription is a result of two important
aspects of its function: its modification of histones and
interaction with other coactivators and DNA binding factors to bind to the enhancer promoter regions [117-119].
The chromatin environment is very important for transcription and the role of PARPs in chromatin remodeling
has been well documented [55,108]. PARP has been
found to associate with the Facilitates of Chromatin Transcription (FACT) complex, a protein complex involved in
chromatin remodeling. Poly (ADP-ribosyl)ation of the
FACT complex prevents the interaction between FACT and
nucleosomes in vitro [120]. As mentioned before, Histone
H1 and H2B are major acceptors of PARP modification
and this modification can also remodel chromatin structure [116]. Specifically poly (ADP-ribosyl)ation of nucleosome structures can cause relaxation of chromatin
structure [116,121,122].
In a recent study, PARP1 was shown to be broadly distributed across the human genome. Furthermore, PARP1 and
histone H1 were shown to have reciprocal roles in regulating gene expression. When there is increased presence of
PARP and decreased presence of H1 at promoter regions
of genes, the genes are activated in 90% of the cases. When
gene promoters had both decreased presence of PARP and
H1, less than 45% of genes were expressed [123]. Tulin
and Spalding reported that PARP can activate the transcription of heat shock proteins in Drosophila by
decondensing chromatin structure [108]. This was in contradiction to the study of Oei et al who showed that poly
(ADP-ribosyl)ation of transcription factors for TATAbinding protein (TBP) or YinYang1 (YY1) prevented these
transcription factors from binding DNA [124]. However,
once TBP or YY1 were bound to DNA, they were immune
to the action of PARP. Therefore, PARP cannot dislodge
TBP or YY1 once they are bound to DNA. In this way,
PARP can prevent transcription in specific parts of the
genome without disturbing ongoing transcription
[60,125,126].
PARP interacts with transcription factors at enhancer and
promoter regions via its involvement with NF-κβ,
[23,78,127,128]. PARP-NF-κβ interactions have impor-
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tant consequences for inflammation. PARP1 deficient
mice cloned by Oliver et al were resistant to endotoxic
shock normally induced by exposure to lipopolysaccaride
(LPS) [102]. This could be a result of decreased expression
of genes controlled by NF-κβ [35,97,126,129,130].
The epigenetic role of PARP extends to other genomic
structures besides histones. Poly (ADP-ribosyl)ation of
the CCCTC-binding factor (zinc finger protein) CTCF
gene, a chromatin insulator encoding protein has been
shown to affect the ability of this protein to interact with
over 140 target sites in mice [107,131-133]. The role of
PARP in controlling the function of the CTCF insulator in
the regulation of the transcriptional states of various genes
further demonstrates the role of PARP in epigenetics
[134,135].
Poly (ADP-ribose) glycohydrolase (PARG) and PARP
interactions
Poly (ADP-ribose) glycohydrolase or PARG is an enzyme
involved in poly (ADP-ribose) metabolism. PARG
removes PAR units from proteins and thus plays an
equally important role as PARP in cellular function.
Though PARG is found in the cytoplasm rather than the
nucleus where PARP is found [136], PARG can be transported between the nucleus and cytoplasm in order to regulate the breakdown of poly (ADP-ribose) [137]. It was
found that a PARG deficiency in mice was lethal because
of an accumulation of poly (ADP-ribose) [138].
Specifically, PARG maintains chromatin structure by
removal of poly(ADP-ribose) and by acting in opposition
to PARP return chromatin to its original state. PARG
accomplishes this by removing PAR groups from histones
and once again allowing histones to form the nucleosome
structure of chromatin [137]. PARG is involved in DNA
repair by regulating the amount of PAR synthesized in
response to DNA damage since excessive accumulation of
PAR may result in cell death [101]. PARG and PARP work
in opposition to each other to modify chromatin structure
[117,122]. When PARP creates transcriptionally active
regions of chromatin, PARG restores chromatin to its original state. However, PARP does not always transcriptionally activate chromatin regions. For instance, in
euchromatin regions, PARP is involved in chromatin
decondensation and promoting transcription while in
heterochromatin regions it could repress transcription
[117]. Knocking out of PARG was found to be lethal in
mouse embryonic cells at day 3 of gestation since PARG is
the primary enzyme involved in breaking down PAR in
cells [138].
Due to its abilities to regulate the ADP-ribose that is
required for protection against DNA damage, PARG is
involved in cellular responses to oxidative stress [139]. In
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a recent study by Fisher et al, PARG was found to cooperate with PARP1 in responding to oxidative damage by regulating XRCC1 at DNA break sites created by oxidative
damage [140]. PARG has also been shown to protect
against cell damage caused by genotoxic or oxidative
stress even at sub-lethal levels by regulating PAR [138].
Role of PARP in germ cell death
Apoptosis is a normal component of mammalian spermatogenesis. It is orchestrated spontaneously during the
entire stages of spermatogenesis in order to produce
mature spermatozoa and to eliminate any abnormal spermatozoa. In fact, a very large number of spermatozoa die
and are eliminated during spermatogenesis. This may be
due to the ability of the Sertoli cells to maintain only a
limited number of germ cells and resulting in the elimination of excess germ cells. Apoptosis may also function to
destroy cells that do not make it past certain cellular
checkpoints [141] Evidence seems to point to the notion
that germ cell death during mitotic and meiotic cell divisions may be needed to eliminate problems such as errors
in chromosomal arrangement during meiosis or unrepaired breaks in DNA. More importantly, apoptosis may
be needed to prevent genetic abnormalities from being
passed onto offspring [142]. In a recent study, Codelia et
al examined which cell death pathway was involved in
pubertal rat spermatogenesis. Using a caspase-8 inhibitor
and a pan-caspase inhibitor they detected significantly
less cleaved PARP and also a reduction in the number of
apoptotic germ cells suggesting that germ cell apoptosis
occurs via the Fas antigen (Fas)-Fas ligand (Fas-FasL) system and that PARP cleavage may play a key role [143].
Not only does PARP have a well-defined role in DNA
repair, but it is also involved in apoptosis. During apoptosis, numerous DNA strand breaks can lead to PARP activation. This activation of PARP may be an attempt by the
dying cell to repair the DNA damage caused by nuclease
activation [129,144,145]. However, this attempt to repair
damage proves futile as PARP is cleaved by caspase-3 into
a catalytic fragment of 89 kDa and DNA binding unit of
24 kDa [61,146]. Therefore, this cleaved version of PARP
could be a biochemical marker of caspase-dependent
apoptosis [147,148].
Deregulation of germ cell death can have important
implications for male fertility. Patients with contralateral
testes exhibit an increased incidence of apoptosis. The
presence of apoptotic markers is high in these patients
especially in spermatocytes, early and late spermatids, and
Sertoli cells [149]. Infertile men with spermatid and spermatocyte maturation arrest and hypospermatogenesis
also show increased apoptosis [150]. Specifically, the FasFasL pathway and active caspase 3 showed increased activity in testes with maturation arrest and Sertoli cell-only
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syndrome (SCOS) [127,151]. Increased rate of apoptosis
seen with these infertility cases may be due to elimination
of germ cells with extensive DNA damage. Tesarik et al
compared men with complete spermiogenesis failure to
another group of azoospermic men who had incomplete
failure of spermiogenesis and were able to show that
apoptotic DNA damage was greater in the latter group
when compared to the former. This increase in DNA damage seen in patients with complete spermiogenesis failure
could be responsible for the low conception success rates
in these cases [152]. In a more recent study, Maymon et al
proposed that the presence of greater PAR levels in human
spermatocytes during maturation arrest could be correlated with the greater occurrence of DNA strand breaks
during impaired spermatogenesis [153].
PARP2 has also been implicated in abnormal spermatogenesis. In a recent study by Dantzer et al, PARP2 deficient male mice were found to have hypofertility [154].
Upon examination of infertile PARP2 null mice, an
increased incidence of testicular apoptosis was found specifically in the spermatocyte and spermatid layers. However, the layers containing spermatogonia and
preleptotene spermatocytes were normal. Chromosome
segregation was abnormal during metaphase I and spindle assembly was also abnormal in these PARP2 deficient
mice. Thus, the decrease in fertility seen in these PARP2null mice could be related to both defective meiosis I and
spermiogenesis [81]. These results make it increasingly
clear that apoptotic markers can be excellent diagnostic
tools for evaluating fertility potential.
Exogenous agents applied to the testes may also activate
caspase-dependent cell death pathway. For example,
when the scrotal temperature was increased in rats over
time, the mitochondria dependent cell death pathway in
the testis was activated. The signaling cascade involved
relocation of Bax, translocation of cytochrome C, activation of caspases, and the cleavage of PARP [155].
Although the precise role of PARP in exogenously induced
apoptosis is not clear, a study of PARP's protein targets
may help elucidate this role. Following exogenous stress,
increase in levels of p53 are considered to be a part of the
mechanism that returns spermatogenesis to normal cycles
following apoptosis. P53 is a downstream protein poly
(ADP-ribosyl)ated by PARP [71,75,156]. Under conditions of inflammation, PARP poly (ADP-ribosyl)ates and
activates NF-κβ in human Sertoli cells [157]. Treatment
with anti-inflammatory agents suppress this cell death
pathway thereby validating the involvement of PARP in
inflammatory responses [158,159]. It remains to be seen
if this anti-inflammatory activity of PARP could also be
applied to germ cells.
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PARP and spermatogenesis
PARP1 has been detected in the nuclei of a variety of tissue
types including the brain, heart, kidney, and testis [121].
PARP2 has been detected in the liver, kidney, spleen, adrenal gland, stomach, intestinal epithelium, thymus, brain
tissue, and testis. PARP2 expression is weaker than that of
PARP1 and is well distinguished [51]. PARP1 has high levels of expression in the basal regions of seminiferous
tubules of developing mice, but has almost no presence in
the luminal region of the seminiferous tubules, suggesting
that PARP1 is down-regulated during the haploid stage of
meiosis [51]. This explains why PARP is expressed significantly during the earlier stages of spermatogenesis. However other reports show that in the rat, the highest
concentrations of PARP1 are seen in primary spermatocytes followed by spermatids as transcription declines in
late stages on maturation [160,161]. In a study by Tramontano et al examining rat primary spermatocytes it was
found that both PARP1 and PARP2 are present in these
germ cells. However, the vast majority of PAR in these rat
primary spermatocytes was produced by PARP1 suggesting possibly different roles of PARP1 and PARP2 in spermatogenesis [107]. Interestingly, PARG has also been
detected in the nuclei of rat primary spermatocytes [160]
suggesting the presence of a mechanism to regulate the
levels of poly (ADP-ribose) in germ cells.
In a recent study using human testicular samples, it was
shown that that the strongest levels of PARP1 were found
in spermatogonia. Presence of poly (ADP-ribose) differed
slightly with the stage of spermatogenesis. Poly (ADPribosyl)ation was strongest in human round and elongating spermatids as well as in a subpopulation of primary
spermatocytes. In contrast, mature spermatids had no
PARP expression or poly (ADP-ribosyl)ation [153]. This is
in accordance with a study in rat germ cells where poly
(ADP-ribose) and NAD levels progressively decreased
from primary to secondary spermatocytes and to a greater
extent in spermatids [74]. This decrease in PARP1 levels
and activity throughout differentiating male germ cells
may be correlated with the changes in chromatin structure
associated with spermatogenesis. The chromatin remodeling steps of spermatogenesis include the replacement of
histones by protamines [162] and a transition from a
supercoiled form of DNA to a non-supercoiled form
[163]. It is during these chromatin remodeling steps of
spermiogenesis that DNA strand breaks can occur. In
human testis, an increase in DNA strand breaks occurs in
100% of elongating spermatids [164]. These breaks were
later demonstrated to be double stranded breaks caused
by topoisomerase II as a result of the unique chromatin
packaging steps that take place during spermatogenesis
[14].
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Meyer-Ficca et al (2005) demonstrated the presence of
poly (ADP-ribose) (PAR) in elongated spermatids of rat
[39]. They showed that during these steps when a high
number of DNA breaks occur directly preceding nuclear
condensation, there is correspondingly a higher amount
of PAR in rat germ cells. Greater PAR formation through
PARP1 and PARP2 action occurs during this phase of spermatogenesis that includes a great deal of chromatin condensation (steps 11-14 of rat spermatogenesis), PAR levels
decrease only when protamines appear in the chromatin.
Thus, PAR formation could be important for repairing
DNA strand breaks during these crucial chromatin remodeling steps of spermatogenesis [39,165]. Furthermore,
PAR formation could also be important for histone modification because not only is there auto-modification of
PARP during spermatogenesis, but much of PARP activity
is targeted towards the testes-specific histone, H1t.
The activation of Histone 2A (H2AX), a biological marker
of DNA breaks, and the poly (ADP-ribose)ylation of histones at break sites may act as markers of such damage
[166]. Thus, the activity of PARP during the chromatin
remodeling steps of spermatogenesis in terms of repairing
double stranded breaks and the poly (ADP-ribosyl)ation
of histones, is critical and disregulation of the chromatin
remodeling steps of spermiogenesis could have serious
consequences for the male gamete [164]. PARP2 knockout mouse was shown to be associated with severely compromised spermatids and delays in elongation process
[154]. Heat stress has been reported to decrease PARP
expression in the rat testis [50]. However heat shock protein was reported to activate the PARP and PAR formation
[92].
The quest to detect PARP in ejaculated spermatozoa has
met with success only recently. Taylor et al did not detect
the presence of PARP1 in human ejaculated sperm samples when analyzing semen for apoptotic markers [167].
However, in a recent study by Jha et al, [168] several isoforms of PARP were detected in ejaculated spermatozoa
including PARP1, PARP2, and PARP9. Immunolocalization patterns showed that PARP was found near the acrosomal regions in sperm heads. Furthermore, a direct
correlation was seen between sperm maturity and the
presence of PARP, i.e., an increased presence of PARP1,
PARP2, and PARP9 was seen in mature sperm when compared to immature sperm. Higher levels of PARP1, PARP2
and PARP9 were seen in ejaculated sperm from fertile
men when compared to infertile men indicating a possible relationship between PARP and male infertility. PARP
activity was modulated to determine its role in the
response to oxidative and chemical damage in sperm. In
the presence of a PARP inhibitor, 3-aminobenzamide,
chemical and oxidative stress-induced apoptosis was
reported to increase by nearly two-fold. This novel finding
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suggests that PARP could play an important role in protecting spermatozoa subjected to oxidative and chemical
damage [168].
PARP and sperm DNA
Recently the importance of DNA damage to sperm of
infertile men has gained attention. It has been shown that
that a higher index of DNA damage can possibly lead to
lower semen quality. In a study involving 322 couples,
when DNA fragmentation exceeded an index of 15%,
there was increased incidence of non-transfer and miscarriages after performing ICSI [169]. Studies such as these
warrant the investigation of factors that may be responsible for maintaining genomic integrity especially in ejaculated spermatozoa. DNA damage repair through PARP
activity has been demonstrated in rat germ cells. Atorino
et al showed that after extensive DNA damage in rat spermatids and spermatocytes caused by radiation and ROS
damage in vivo, a PARP inhibitor caused a delay in DNA
damage repair [40]. They were able to demonstrate up to
a 3-fold increase in PARP activation as cells recovered
from these damaging agents [60,125,126]. The main difference between spermatids and primary spermatocytes
was that only spermatids showed detectable PAR production after genotoxic stress. Atorino et al hypothesized that
primary spermatocytes did not show the same degree of
response possibly due to the different chromatin states of
these two germ cells. Thus, PARP activity in response to
genotoxic stress may be important for preventing mutations from accumulating and being passed on to offspring
[40].
Though the role of PARP in repairing DNA damage in
ejaculated spermatozoa has yet to be thoroughly investigated, it has been found that DNA damage caused by
sperm cryopreservation can be repaired through PARP
activity. In a study by Kopeika et al, cryopreserved sperm
from loach (fresh water fish related to carp) were used to
fertilize eggs and the embryos were exposed to a PARP
inhibitor [170]. It was found that survival was significantly decreased in embryos exposed to PARP inhibitors
when compared to control. This study suggests a possible
role for PARP in repairing paternal DNA damage and it
also showed that it was possible for the oocyte to repair
this damage even in presence of PARP inhibition [170].
Cryopreservation is not the only threat to genomic integrity. It is still controversial whether malignancy itself is the
cause of chromatin damage in mature spermatozoa. In a
study analyzing 75 men with various types of testicular
and non-testicular cancers, the degree of DNA fragmentation did not differ between types of cancer. But surprisingly, the levels of DNA fragmentation in cancer patients
were similar to the levels found in infertile men [171].
Another study found that patients with testicular cancer
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and Hodgkin's Lymphoma were normospermic, but had
increased levels of DNA damage along with decreased
chromatin compaction [172]. However, a third study in
the same year hypothesized that malignancy alone was
not responsible for increased DNA damage seen in sperm.
This study showed that thawed sperm samples from cancer patients had similar levels of DNA fragmentation to
that of sperm with low freezability collected from healthy
donors. This study attributed the increased sperm DNA
damage seen in the decreased freezability of these semen
specimens and not to malignancy [173].
affected family due to the expansion of these repeats.
Deletion of MSH2 suggests an active role for MSH2 during
extensive DNA repair [179-182]. Quite interestingly, caffeine may lead to inactivation of H2AX and non-homologous end-joining (NHEJ) DNA repair [183]. Impairment
in DNA repair during spermiogenesis may result in persistent double stranded breaks in mature spermatozoa.
Further investigation may provide important clues regarding the consequences of the endogenous DNA strand
breaks and repair in spermatids and mature spermatozoa
[184].
Nonetheless, cancer patients are advised to freeze sperm
prior to therapy as an option to preserve their fertility
potential. Patients undergoing radiotherapy have shown a
temporary increase in the sperm with DNA strand breaks
and a decrease in fertility despite having normal sperm
concentrations [42]. Chemotherapy does not produce the
same deleterious effects as radiotherapy in its initial
phase. Decrease in sperm DNA fragmentation is generally
seen after 3 or more cycles of chemotherapy [174]. Chemotherapy (especially alkylating agents) and radiotherapy,
even in low doses, can damage the seminiferous epithelium and impair spermatogenesis in both children and
adults [175].
Down regulation of DNA repair genes such as Ogg1
(involved in base excision repair), Rad54 (involved in
double-strand break repair) and Xpg (involved in nucleotide excision repair) has been reported using global
genome expression by DNA microarray following exposure to heat stress at 43°C [30]. Heat stress induced by
cryptorchidism appears to result in decreased expression
of DNA polymerase B and DNA ligase III both of which
are involved in the final stages of DNA repair [185,186].
Apart from treatment by either chemo- or radiotherapy,
malignancy itself causes a significant threat to sperm DNA
damage. This could mean that cryopreservation of sperm
prior to therapy may not be sufficient to preserve fertility
[174]. Instead, therapeutic options such as modification
of PARP activity could be used in order to retain genomic
integrity under threats of malignancy and radiotherapy to
eliminate the low quality spermatozoa with DNA damage
[176,177].
Sperm DNA damage repair defects
DNA polymerase activity in non-replicating cells is associated with DNA repair. Consequently, increase in apoptotic markers seen in the semen of infertile men may also
be an indicator of increase DNA repair activity [15]. Evidence from the literature indicates that DNA repair systems may play a role during spermiogenesis. Elements of
base excision repair (BER) have been identified in elongated spermatids [178]. Mismatch repair (MMR) involving the mutS homolog 2 (MSH2) proteins has a role in
spermiogenesis. Interestingly, in a mouse model for Huntington disease, deletion of MSH2 in Huntington disease
abolished
trinucleotide
cytosine-adenine-guanisine
(CAG) repeat expansion between round spermatids and
spermatozoa. CAG, is a DNA mutation responsible for
causing any type of disorder categorized as a trinucleotide
repeat disorder. Presence of CAG repeat expansion may
explain the earlier onset of the disease and the severity of
the symptoms through successive generations of an
PARP - a new marker in ejaculated spermatozoa
The role of PARP in DNA repair (Figure 2) and its presence
during stages of spermatogenesis suggest that it is
involved in maintaining genomic integrity in ejaculated
sperm. However, the presence of PARP has only recently
been shown in ejaculated sperm samples. Furthermore,
Jha et al have suggested a correlation with the presence of
PARP and male fertility [168]. This study suggested that
the decreased presence of PARP in the sperm of infertile
men could be the cause of increased DNA damage seen in
poor quality semen samples. DNA damage repair in germ
cells as mediated by PARP is therefore as yet unexplored
confounder of male fertility. Further studies are needed to
fully explore the role of PARP in DNA repair especially in
reproductive medicine [50-52,55,187]. The existing methods of detecting infertility from semen samples are quantitative methods involving the count and observation of
sperm and are dubious due to the constantly changing
'normal' seminal values. A qualitative method would thus
serve as a more reliable method of detecting infertility
[125,162]. In view of this, the detection of apoptotic
markers such as caspase and phosphatidylserine (PS) have
been successfully correlated with a variety of infertility
conditions; however, the use of PARP as an apoptotic
marker has not been fully investigated.
Taylor et al found greater caspase activity in low motility
sperm samples from infertile men when compared to
those with high motility [167]. The active caspase
enzymes have been localized in the human spermatozoa
predominantly in the post acrosomal region (caspase 8, 1
and 3) [188-190] or in the mid-piece [191]. A significant
positive correlation between in-situ active caspase-3 in the
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sperm midpiece and DNA fragmentation was observed in
the low motility fractions of patients, suggesting that caspase-dependent apoptotic mechanisms could originate in
the cytoplasmic droplet or within mitochondria and function in the nucleus [192]. These data suggest that in some
ejaculated sperm populations, caspases are present and
may function to increase PS translocation and DNA fragmentation. Furthermore fluorescence staining of active
caspases localized the enzymes mainly to the postacrosomal region in sperm from donors. This pattern differed
slightly from that of patients, in whom additional cytoplasmic residues were found to be highly positive [193].
In an interesting study published by Falerio and Lazebnik
in 2000, question as to how caspase 3 which is usually
cytoplasmic gains access to its nuclear targets was examined [194]. These investigators suggested that caspase-3
was actively transported to the nucleus through the
nuclear pores. They found that caspase-9, which is activated earlier than caspase-3, directly or indirectly inactivated nuclear transport and increased the diffusion limit
of the nuclear pores. This increase allowed caspase-3 and
other molecules that could not pass through the nuclear
pores in living cells to enter or leave the nucleus during
apoptosis by diffusion. Hence they suggested that caspase9 contributes to cell disassembly by disrupting the nuclear
cytoplasmic barrier [194].
Unlike somatic cells, early studies were not able to detect
PARP1 or AIF (which is activated by PARP) in ejaculated
sperm [106,167,195,196]. Similarly, the presence of
cleaved PARP could not be detected in ejaculated sperm
[197]; although PARP activity was demonstrated in the
testis [198]. We studied the localization of the PARP in
mature and immature spermatozoa in fertile and infertile
men [168]. Mahfouz et al were the first to demonstrate the
presence of cleaved PARP in ejaculated spermatozoa.
When these sperm samples were exposed to PARP inhibitors after chemical and oxidative stress, there was a
decreased incidence of apoptosis [199]. Although these
authors did not study PARP and caspase 3 co-localization,
they proposed that PARP cleavage may occur by activated
caspase 3 located in the post acrosomal region. It would
be worthwhile to replicate these findings in other mammals and investigate the use of cleaved PARP as a diagnostic tool to predict/detect male infertility.
PARP and oxidative stress
Oxidative stress (OS) occurs when there is an increase in
ROS levels and/or a decrease in the activity of the antioxidant enzymes that scavenge these harmful free radicals
[200,201]. Such conditions of oxidative stress arise when
germ cells are faced with biological (such as lipopolysaccharide, LPS) or chemical stressors (e.g. environmental
toxicants, endocrine disruptors etc.) [20,31,202-204]. The
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extent of oxidative stress induced depends on the dose
and duration of exposure to the stressor [204]. Oxidative
stress can cause modification of proteins associated with
developing spermatozoa and cause the premature release
of sperm from seminiferous tubules [205]. Even a transient state of oxidative stress, spanning a few hours has
been shown to bring about protein changes and stimulate
a caspase-3-mediated cell death pathway and apoptosis
[43,206]. In the reproductive milieu, oxidative stress is
also linked to inflammation particularly since inflammatory cytokines dramatically arrest spermatogenesis and
may lead to infertility [207]. However, the most important effect is the ability of oxidative stress to cause DNA
damage. PARP responds to all three of these changes that
can occur in the cell as a result of oxidative damage. However, there is a great deal of variability in PARP activation
as a result of this type of stress depending on the metabolic stage of the cell or its microenvironment [208-210].
As a result of its interaction with NF-κβ, PARP has an
important role in the inflammation process [78,102]. In
response to DNA damage caused by oxidative species,
PARP1 recruits the DNA repair protein XRCC1 to the sites
of the damage [211]. In addition to causing damage to
DNA, oxidative species can harm histones wherein PARP
activates the 20S proteosome involved in breaking down
oxidatively damaged histones. Also, in response to oxidative stress caused by exposure of histones to hydrogen peroxide, a complex is formed by the binding of PARP, poly
(ADP-ribose), and the nuclear proteosome [133,212].
This complex formation could be important because a
condensed chromatin structure may protect DNA from
strand breaks induced by hydroxyl radicals [196,213].
In conditions of oxidative stress-induced necrosis in Bax-/
- Bak-/- (a proapoptotic protein that regulates the intrinsic
apoptotic pathway) mouse embryonic fibroblasts, there is
an activation of PARP1. PARP1-catalysed poly (ADP-ribosyl)ation causes a depletion of ATP, which promotes the
autophagy of these necrotic embryonic cells [214]. PARP1
has been implicated in the repair of DNA damaged by
estradiol in human estrogen-receptor-negative (ER-/-)
breast cancer cells. Treatment of these breast cancer cells
with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which
is itself an estrogenic toxicant, altered the expression of
enzymes responsible for the bio-activation of estrogen
leading to DNA damage, PARP1 activation and DNA
repair. Thus, the apoptosis of human ER -/breast cancer
cells was prevented by TCDD-induced activation of
PARP1 and aided the survival of these cancer cells [215].
Interestingly, administration of TCDD caused the expression of cDNA encoding a 75 kDa protein that had
sequence similarity with PARP. This protein, renamed as
TCDD-inducible PARP (TiPARP) possessed catalytic activity similar to PARP [216]. However, the role of TiPARP on
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chromosome stability, DNA repair and apoptosis are yet
to be elucidated.
PARP and ageing
The ageing process also takes its toll on DNA, which can
in turn, affect the fertility potential of a male. As discussed
earlier, PARP is also involved in ageing through its role in
immune responses, telomere maintenance, DNA repair,
spindle assembly, and cell death [217]. In a recent study,
El-Domyati et al collected sperm samples from fertile men
of various age groups and quantified the differences in
PARP1 presence and PARP activity [198]. The expression
of PARP1 and its DNA repair partner, XRCC1 were higher
in spermatocytes of older men while the Sertoli cells of
these men showed higher levels of PAR. Apoptosis was
increased in older men who showed more active caspase3 and cleaved PARP1 in the spermatogonia and spermatocytes. This general increase in PARP1 and DNA repair
enzymes could be associated with the declining DNA
integrity as a result of age [198].
Chromosomal stability is vital for the survival of an
organism and chromosomal instability increases with the
age of an organism and is considered a symptom of ageing. PARP is essential for chromosomal stability through
its role in DNA repair. PARP activity may influence ageing
by maintaining genomic stability through DNA repair, telomere maintenance, spindle stability, and cell death
[209,217-219]. Under physiological conditions, both
PARP1 and PARP2 affect telomere functioning by binding
to telomere repeat binding factor II (TRFII) and affecting
its ability to bind to telomere regions [220-222]. PARP1 is
also found at telomere regions of DNA that is damaged by
genotoxic agents and it may play a role in preventing damage to genomic stability [221]. PARP1 deficient mice
showed greater incidence of chromosomal aberrations,
polyploidy and telomere shortening. When PARP was
reintroduced in the form of cDNA, chromosomal integrity
was restored [223,224].
Biological role of PARP in male fertility
PARP plays a crucial role in maintaining genomic integrity
in a variety of cell types and perhaps nowhere is this
genomic integrity more important than in germ cells.
Cases of male infertility are associated with abnormal
sperm chromatin and DNA structure. The problems that
arise in genomic integrity of sperm come from a variety of
sources including spermatogenesis defects, abortive apoptosis, problems with spermatid maturation, and oxidative
stress [22,225]. Problems in spermatogenesis could
include double strand breaks that are not resolved after
crossing over during meiosis I [22]. Although there has
not been any clear association between apoptotic markers
and DNA fragmentation in mature male gametes, it is possible that incomplete apoptosis could be a cause of such
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DNA fragmentation [22,226]. Maturation of spermatids
involves chromatin remodeling steps that involve necessary DNA strand breaks and thus could be a source of
unresolved breaks. Lastly, ROS levels and oxidative stress
has been extensively investigated in male infertility, and
in light of the activation of PARP-induced apoptosis pathways in oxidative stress conditions, may provide an explanation for the role of PARP in male fertility.
Thus, at the time of writing this review, the role of PARP
in male fertility is not as well defined as its role in other
cellular processes. However, there is enough evidence
such as detection of PARP in the testis, during spermatogenesis, and in ejaculated spermatozoa to suggest that
such a role exists [168,199]. Furthermore, the role of
PARP as an important DNA repair enzyme could
empower it with maintaining the genomic integrity of
sperm. Similarly, the role of PARP in cell death pathways
may have important implications for its role in the elimination of abnormal spermatozoa during the processes of
spermatogenesis [227].
Potential therapeutic applications of PARP
The key role of PARP in cell death has made it an attractive
candidate in cancer therapies [157]. It is based on the simple idea that inhibiting DNA repair in malignant cells
exposed to chemotherapy will kill off these cancerous
cells due to the large amounts of DNA damage that will
accumulate if PARP is inactivated [228]. Non-malignant
cells will not be susceptible to cell death at these low doses
of chemotherapy. Thus PARP inhibitors could provide a
means to sensitize cancerous cells to chemotherapy and
be developed as an adjuvant to chemotherapy [229]. An
alternate strategy being explored is that of inactivating
PARP through cleavage to attain the same end result, i.e.,
accumulation of damaged DNA in cancerous cells causing
them to die faster [227,230].
PARP modulation may not only prove useful in cancer
therapies, but also in dangerous inflammatory processes.
The role of PARP in inflammation especially through the
recruitment of NF-κβ and through its role in responding
to oxidative stress produced by the inflammatory processes make it a powerful target for anti-inflammatory therapy [157]. The use of PARP inhibitors as therapeutics in
conditions such as cerebral ischemia and other inflammation-induced conditions may be explored [159,219]. It
still remains to be seen whether PARP can provide a therapy for male infertility. PARP inhibition may protect
against chemically induced injury of ejaculated spermatozoa in vitro, but is not effective against damage induced
by oxidative stress [199]. It is also possible that PARP inhibition may have a potential role in testicular cancer as well
as cancer that may have spread to the testes [109]. Inflammatory processes as result of infections could also be
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another area to explore in terms of PARP and male fertility.
Conclusion
PARP homologues have diverse role(s) in spermatogenesis and in ejaculated sperm. PARP expression is associated
with sperm maturity in proven fertile men. Morphogenesis and changes during the spermatid stages result in
removal of the cytoplasm from the fully mature, functionally active spermatozoa. However, many proteomic studies, other than those published by our group (Jha et al
2009) have shown differences in protein expression in
spermatozoa from infertile males. Although the mature
spermatozoa are transcriptionally inactive, some reports
suggest that there may be enough mRNA in these mature
spermatozoa, although their exact function and role is
unclear and is being investigated. PARP inhibition may be
used as an in vitro treatment in certain conditions such as
oxidative stress and/or chemically induced death of spermatozoa with damaged DNA. Therefore these spermatozoa may not have the ability to fertilize or produce
healthy embryo as the oocyte repair system may be inadequate to correct such high DNA damage. PARP modulation using kinase activators or inhibitors may have a
future beneficial role in infertile patients exhibiting sperm
DNA damage. This could pave the way for future studies
to elucidate the role of PARP in other conditions resulting
in sperm DNA damage. Cleaved PARP, which is activated
during apoptosis, could serve as an apoptotic marker for
differentiating healthy spermatozoa from apoptotic ones.
In addition, the anti-tumor properties of PARP could provide new strategies to preserve fertility in cancer patients
even after genotoxic stresses like radiation. The possibility
of using DNA damaged sperm in ART especially in ICSI
needs careful evaluation. PARP may hold the key to a better understanding of these repair mechanisms inherent in
spermatozoa and the importance of such mechanisms in
producing healthy pregnancies.
List of abbreviations
AIF: Apoptosis inducing factor; AMD: Auto modification
domain; ADPR: ADP ribose; AP: Apurinic-apyrimidinic
endonuclease; ART: Assisted reproductive technologies;
BER: Base excision repair; BRCA-1 CT: Breast cancer-1,
human oncogene, C-Terminus; Bub3: Budding uninhibited by benzimidazoles 3; CAG: Tri-nucleotide (CytosineAdenine- Guanine) CD: Catalytic domain; CTCF: CCCTCbinding factor (zinc finger protein); DBD: DNA binding
domain; DBD: DNA binding domain; ERK: Extracellular
signal-regulated kinases; Fas-FasL, Fas antigen (Fas)/Fas
ligand (FasL); H2AX: One of several genes coding for histone H2A; ICSI: Intracytoplasmic sperm injection; LPS:
Lipopolysaccaride; MALDI-TOF-TOF: Matrix-assisted laser
desorption/ionization
time-of-flight/time-of-flight;
MSH2: MutS homolog 2; NAD: Nicotinamide adenine
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dinucleotide; NBS1: Nijmegen Breakage Syndrome 1; NFκβ: Nuclear factor-kappa β; NHEJ: Non-homologous endjoining; NLS: Nuclear localization signal; PAR: Poly (ADPribose); PARG: Poly (ADP-ribose) glycohydrolase; PARP:
Poly (ADP-ribose) polymerase; Rad54: A gene linked to
chromosome 1p32, encodes for a protein known to be
involved in the homologous recombination and repair of
DNA; ROS: Reactive oxygen species; SCOS: Sertoli cell
only syndrome; SIRT1: Silent information regulator gene
in human affect the metabolism and inflammation; TBP:
TATA-binding protein; TCDD: 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin; TRFI-I: Telomere repeat binding factor
II, I; WWE domains, Domain associated with protein-protein interaction; XRCC1: X-ray repair complementing
defective repair in Chinese hamster cells 1; YY1:
YinYang1.
Competing interests
No financial competing interests (political, personal, religious, ideological, academic, intellectual, commercial or
any other) to declare in relation to this paper.
Authors' contributions
AA provided substantial contribution ranging from study
idea, design, information collection, critical review of the
final paper. RZM participated in the original idea,
medline search, drafting and finalizing the paper. RKS
conceived the study, participated in the study design compilation of the contents and critical review of the paper.
OS participated in compilation of the information and
critical review of the paper. DM carried out the literature
search, compilation of the information. PPM participated
in the design of the study and helped finalize the paper.
All authors read and approved the final manuscript.
Acknowledgements
Authors are grateful for the support from the Center for Reproductive
Medicine, Cleveland Clinic.
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