Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS... more Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS-CoV-2 infection-induced COVID-19. We therefore analyzed the expression of DNA repair genes in publicly available transcriptomic datasets of COVID-19 patients and found that the level of NEIL2, an oxidized base specific mammalian DNA glycosylase, is particularly low in the lungs of COVID-19 patients displaying severe symptoms. Downregulation of pulmonary NEIL2 in CoV-2-permissive animals and postmortem COVID-19 patients validated these results. To investigate the potential roles of NEIL2 in CoV-2 pathogenesis, we infected Neil2-null (Neil2−/−) mice with a mouse-adapted CoV-2 strain and found that Neil2−/− mice suffered more severe viral infection concomitant with increased expression of proinflammatory genes, which resulted in an enhanced mortality rate of 80%, up from 20% for the age matched Neil2+/+ cohorts. We also found that infected animals accumulated a significant amount of damage...
Mammalian polynucleotide kinase 3’-phosphatase (PNKP) is a dual-function DNA end-processing enzym... more Mammalian polynucleotide kinase 3’-phosphatase (PNKP) is a dual-function DNA end-processing enzyme with 3’-phosphatase and 5’-kinase activities, which generate 3’-OH and 5’-phosphate termini respectively, as substrates for DNA polymerase and DNA ligase to complete DNA repair. PNKP is thus involved in multiple DNA repair pathways, including base excision (BER), single-strand break (SSBR), and double-strand break repair (DSBR). However, little is known as to how PNKP functions in such diverse repair processes, which involve distinct sets of proteins. In this study, we report that PNKP is acetylated at two lysine (K142 and K226) residues. While K142 (AcK142) is constitutively acetylated by p300, CBP acetylates K226 (AcK226) only after DSB induction. Co-immunoprecipitation analysis using antibodies specific for PNKP peptides containing AcK142 or AcK226 of PNKP showed that AcK142-PNKP associates only with BER/SSBR, and AcK226 PNKP only with DSBR proteins. Although acetylation at these re...
The primary cause of morbidity and mortality from infection with respiratory syncytial virus (RSV... more The primary cause of morbidity and mortality from infection with respiratory syncytial virus (RSV) is the excessive innate immune response(s) (IIR) in which reactive oxygen species (ROS) play key role(s). However, the mechanisms for these processes are not fully understood. We hypothesized that expressions of IIR genes are controlled by the ROS-generated epigenetic-like mark 7,8-dihydro-8-oxo(d)guanine (8-oxo(d)Gua) and 8-oxoguanine DNA glycosylase1 (OGG1). Here, we report that ROS not only generates intrahelical 8-oxo(d)Gua, but also enzymatically disables OGG1 in RSV-infected human airway epithelial cells and mouse lungs. OGG1 bound to 8-oxo(d)Gua in gene regulatory sequences promotes expression of IIR genes, and consequently exacerbates lung inflammation, histological changes, and body weight loss of experimental animals. Pharmacological inhibition of OGG1 substrate binding decreased expression of RSV-induced chemokine and cytokines and significantly lessened clinical symptoms. R...
Respiratory syncytial virus (RSV) infection induces an oxidizing environment linked to increased ... more Respiratory syncytial virus (RSV) infection induces an oxidizing environment linked to increased viral load, expression of pro-inflammatory genes, and excessive lung inflammation. The mechanisms of how reactive oxygen species (ROS) promotes viral gene expression have remained largely elusive. Here we show that nascent (n)RNAs of RSV acquire 8-oxo-7,8-dihydroguanine (8-oxo(r)Gua) -a covalently modified guanine base in their 5’-UTR peritranscriptionally, while paired with the 3’-terminus of viral gene(s). 8-oxo(r)Gua is bound by 8-oxoguanine DNA glycosylase1 (OGG1), a complex that physically interacts with and recruits the anti-terminator protein M2-1 to increase viral gene transcription. Knockdown of OGG1 (but not other DNA glycosylases) or inhibition of its binding, significantly decreased RSV mRNA, protein levels and yield of progeny in cultured cells and airways. Collectively, these data suggest that Gua oxidation in vRNA, serves as an epitranscriptomic mark that repurposes OGG1 t...
Colorectal cancer (CRC) is the third most prevalent and deadly cancer. Approximately, 15-20 % of ... more Colorectal cancer (CRC) is the third most prevalent and deadly cancer. Approximately, 15-20 % of CRCs display microsatellite instability (MSI); however, the majority (80–85%) of cases are sporadic and known as microsatellite stable (MSS). Several recent studies indicated that infection and uncontrolled inflammation initiate DNA damage and lead to cancer progression. One of the major microbes, Fusobacterium nucleatum (Fn) is highly associated with CRC, but the role of DNA repair in microbe-associated CRC has been largely unknown. Here we show that NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated among all the key DNA repair proteins involved in various DNA repair pathways, after infection of Fn with stem-cell-based enteroid-derived monolayers (EDMs) of murine and human healthy subjects. Furthermore, following Fn infection, NEIL2-null mouse-derived EDMs showed significantly higher level of DNA damage, including double strand breaks, and inflammatory cyt...
Proceedings of the National Academy of Sciences, 2020
Significance Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease with no effectiv... more Significance Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease with no effective treatments. SCA3 is etiologically linked to an abnormal polyglutamine (polyQ) tract at the C terminus of Ataxin-3 (ATXN3). How this polyQ stretch causes SCA3 pathology remains elusive. Here we provide evidence that wild-type ATXN3 plays an important role in error-free repair of DNA double-strand breaks in the transcribed genes. In contrast, mutant ATXN3 blocks the activity of a DNA end-processing enzyme, polynucleotide kinase 3′-phosphatase (PNKP), leading to progressive accumulation of double-strand breaks and abrogation of global transcription. Since PNKP overexpression in Drosophila rescued the SCA3 phenotype, this promising therapeutic avenue for SCA3 is worth exploring.
The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithel... more The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; th...
How huntingtin (HTT) triggers neurotoxicity in Huntington’s disease (HD) remains unclear. We repo... more How huntingtin (HTT) triggers neurotoxicity in Huntington’s disease (HD) remains unclear. We report that HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP). This complex senses and facilitates DNA damage repair during transcriptional elongation, but its functional integrity is impaired by mutant HTT. Abrogated PNKP activity results in persistent DNA break accumulation, preferentially in actively transcribed genes, and aberrant activation of DNA damage-response ataxia telangiectasia-mutated (ATM) signaling in HD transgenic mouse and cell models. A concomitant decrease in Ataxin-3 activity facilitates CBP ubiquitination and degradation, adversely impacting transcription and DNA repair. Increasing PNKP activity in mutant cells improves genome integrity and cell survival. These findings suggest a ...
8-Oxoguanine DNA glycosylase 1 (OGG1) initiates the base excision repair pathway by removing one ... more 8-Oxoguanine DNA glycosylase 1 (OGG1) initiates the base excision repair pathway by removing one of the most abundant DNA lesions, 8-oxo-7,8-dihydroguanine (8-oxoG). Recent data showed that 8-oxoG not only is a pro-mutagenic genomic base lesion, but also functions as an epigenetic mark and that consequently OGG1 acquire distinct roles in modulation of gene expression. In support, lack of functional OGG1 in Ogg1 mice led to an altered expression of genes including those responsible for the aberrant innate and adaptive immune responses and susceptibility to metabolic disorders. Therefore, the present study examined stimulus-driven OGG1-DNA interactions at whole genome level using chromatin immunoprecipitation (ChIP)-coupled sequencing, and the roles of OGG1 enriched on the genome were validated by molecular and system-level approaches. Results showed that signaling levels of cellular ROS generated by TNFα, induced enrichment of OGG1 at specific sites of chromatinized DNA, primarily in...
A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-ri... more A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-rich clusters; guanines are the bases most susceptible to oxidative modification(s). Consequently, 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the most abundant base lesions in promoters and is primarily repaired via the 8-oxoguanine DNA glycosylase-1 (OOG1)-initiated base excision repair pathway. In view of a prompt cellular response to oxidative challenge, we hypothesized that the 8-oxoG lesion and the cognate repair protein OGG1 are utilized in transcriptional gene activation. Here, we document TNFα-induced enrichment of both 8-oxoG and OGG1 in promoters of pro-inflammatory genes, which precedes interaction of NF-κB with its DNA-binding motif. OGG1 bound to 8-oxoG upstream from the NF-κB motif increased its DNA occupancy by promoting an on-rate of both homodimeric and heterodimeric forms of NF-κB. OGG1 depletion decreased both NF-κB binding and gene expression, whereas Nei-like glycosyl...
Amphotericin B and anidulafungin are widely used antifungal drugs for the treatment of systemic a... more Amphotericin B and anidulafungin are widely used antifungal drugs for the treatment of systemic and serious mycoses.
Journal of immunology (Baltimore, Md. : 1950), 2014
8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanin... more 8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG) via the DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in the genomic DNA leads to genetic instability and carcinogenesis and is thought to contribute to the worsening of various inflammatory and disease processes. However, the disease mechanism is unknown. In this study, we proposed that the mechanistic link between OGG1-BER and proinflammatory gene expression is OGG1's guanine nucleotide exchange factor activity, acquired after interaction with the 8-oxoG base and consequent activation of the small GTPase RAS. To test this hypothesis, we used BALB/c mice expressing or deficient in OGG1 in their airway epithelium and various molecular biological approaches, including active RAS pulldown, reporter and Comet assays, small interfering RNA-mediated depletion of gene expression, quantitative RT-PCR, and immunoblotting. We report that the OGG1-initiated rep...
DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative st... more DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and…
Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base dam... more Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base damage and DNA strand breaks, has a second activity as a transcriptional regulator that binds to several trans -acting factors. APE1 overexpression is often observed in tumor cells and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to such agents. Because the involvement of APE1 in repairing the DNA damage induced by many of these drugs is unlikely, drug resistance may be linked to…
A near-isogenic line (NIL) into which low-molecular-weight glutenin subunits (LMW-GSs) were intro... more A near-isogenic line (NIL) into which low-molecular-weight glutenin subunits (LMW-GSs) were introduced from a Canadian Western Extra-Strong wheat cultivar (Triticum aestivum L.), ‘Glenlea’, into a Japanese spring wheat cultivar, ‘Harunoakebono’, had a much better bread-making quality than does Harunoakebono. LMW-GSs associated with good bread-making quality of the NIL and the allelic LMW-GS in Harunoakebono were monitored by two-dimensional polyacrylamide gel
Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS... more Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS-CoV-2 infection-induced COVID-19. We therefore analyzed the expression of DNA repair genes in publicly available transcriptomic datasets of COVID-19 patients and found that the level of NEIL2, an oxidized base specific mammalian DNA glycosylase, is particularly low in the lungs of COVID-19 patients displaying severe symptoms. Downregulation of pulmonary NEIL2 in CoV-2-permissive animals and postmortem COVID-19 patients validated these results. To investigate the potential roles of NEIL2 in CoV-2 pathogenesis, we infected Neil2-null (Neil2−/−) mice with a mouse-adapted CoV-2 strain and found that Neil2−/− mice suffered more severe viral infection concomitant with increased expression of proinflammatory genes, which resulted in an enhanced mortality rate of 80%, up from 20% for the age matched Neil2+/+ cohorts. We also found that infected animals accumulated a significant amount of damage...
Mammalian polynucleotide kinase 3’-phosphatase (PNKP) is a dual-function DNA end-processing enzym... more Mammalian polynucleotide kinase 3’-phosphatase (PNKP) is a dual-function DNA end-processing enzyme with 3’-phosphatase and 5’-kinase activities, which generate 3’-OH and 5’-phosphate termini respectively, as substrates for DNA polymerase and DNA ligase to complete DNA repair. PNKP is thus involved in multiple DNA repair pathways, including base excision (BER), single-strand break (SSBR), and double-strand break repair (DSBR). However, little is known as to how PNKP functions in such diverse repair processes, which involve distinct sets of proteins. In this study, we report that PNKP is acetylated at two lysine (K142 and K226) residues. While K142 (AcK142) is constitutively acetylated by p300, CBP acetylates K226 (AcK226) only after DSB induction. Co-immunoprecipitation analysis using antibodies specific for PNKP peptides containing AcK142 or AcK226 of PNKP showed that AcK142-PNKP associates only with BER/SSBR, and AcK226 PNKP only with DSBR proteins. Although acetylation at these re...
The primary cause of morbidity and mortality from infection with respiratory syncytial virus (RSV... more The primary cause of morbidity and mortality from infection with respiratory syncytial virus (RSV) is the excessive innate immune response(s) (IIR) in which reactive oxygen species (ROS) play key role(s). However, the mechanisms for these processes are not fully understood. We hypothesized that expressions of IIR genes are controlled by the ROS-generated epigenetic-like mark 7,8-dihydro-8-oxo(d)guanine (8-oxo(d)Gua) and 8-oxoguanine DNA glycosylase1 (OGG1). Here, we report that ROS not only generates intrahelical 8-oxo(d)Gua, but also enzymatically disables OGG1 in RSV-infected human airway epithelial cells and mouse lungs. OGG1 bound to 8-oxo(d)Gua in gene regulatory sequences promotes expression of IIR genes, and consequently exacerbates lung inflammation, histological changes, and body weight loss of experimental animals. Pharmacological inhibition of OGG1 substrate binding decreased expression of RSV-induced chemokine and cytokines and significantly lessened clinical symptoms. R...
Respiratory syncytial virus (RSV) infection induces an oxidizing environment linked to increased ... more Respiratory syncytial virus (RSV) infection induces an oxidizing environment linked to increased viral load, expression of pro-inflammatory genes, and excessive lung inflammation. The mechanisms of how reactive oxygen species (ROS) promotes viral gene expression have remained largely elusive. Here we show that nascent (n)RNAs of RSV acquire 8-oxo-7,8-dihydroguanine (8-oxo(r)Gua) -a covalently modified guanine base in their 5’-UTR peritranscriptionally, while paired with the 3’-terminus of viral gene(s). 8-oxo(r)Gua is bound by 8-oxoguanine DNA glycosylase1 (OGG1), a complex that physically interacts with and recruits the anti-terminator protein M2-1 to increase viral gene transcription. Knockdown of OGG1 (but not other DNA glycosylases) or inhibition of its binding, significantly decreased RSV mRNA, protein levels and yield of progeny in cultured cells and airways. Collectively, these data suggest that Gua oxidation in vRNA, serves as an epitranscriptomic mark that repurposes OGG1 t...
Colorectal cancer (CRC) is the third most prevalent and deadly cancer. Approximately, 15-20 % of ... more Colorectal cancer (CRC) is the third most prevalent and deadly cancer. Approximately, 15-20 % of CRCs display microsatellite instability (MSI); however, the majority (80–85%) of cases are sporadic and known as microsatellite stable (MSS). Several recent studies indicated that infection and uncontrolled inflammation initiate DNA damage and lead to cancer progression. One of the major microbes, Fusobacterium nucleatum (Fn) is highly associated with CRC, but the role of DNA repair in microbe-associated CRC has been largely unknown. Here we show that NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated among all the key DNA repair proteins involved in various DNA repair pathways, after infection of Fn with stem-cell-based enteroid-derived monolayers (EDMs) of murine and human healthy subjects. Furthermore, following Fn infection, NEIL2-null mouse-derived EDMs showed significantly higher level of DNA damage, including double strand breaks, and inflammatory cyt...
Proceedings of the National Academy of Sciences, 2020
Significance Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease with no effectiv... more Significance Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease with no effective treatments. SCA3 is etiologically linked to an abnormal polyglutamine (polyQ) tract at the C terminus of Ataxin-3 (ATXN3). How this polyQ stretch causes SCA3 pathology remains elusive. Here we provide evidence that wild-type ATXN3 plays an important role in error-free repair of DNA double-strand breaks in the transcribed genes. In contrast, mutant ATXN3 blocks the activity of a DNA end-processing enzyme, polynucleotide kinase 3′-phosphatase (PNKP), leading to progressive accumulation of double-strand breaks and abrogation of global transcription. Since PNKP overexpression in Drosophila rescued the SCA3 phenotype, this promising therapeutic avenue for SCA3 is worth exploring.
The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithel... more The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; th...
How huntingtin (HTT) triggers neurotoxicity in Huntington’s disease (HD) remains unclear. We repo... more How huntingtin (HTT) triggers neurotoxicity in Huntington’s disease (HD) remains unclear. We report that HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP). This complex senses and facilitates DNA damage repair during transcriptional elongation, but its functional integrity is impaired by mutant HTT. Abrogated PNKP activity results in persistent DNA break accumulation, preferentially in actively transcribed genes, and aberrant activation of DNA damage-response ataxia telangiectasia-mutated (ATM) signaling in HD transgenic mouse and cell models. A concomitant decrease in Ataxin-3 activity facilitates CBP ubiquitination and degradation, adversely impacting transcription and DNA repair. Increasing PNKP activity in mutant cells improves genome integrity and cell survival. These findings suggest a ...
8-Oxoguanine DNA glycosylase 1 (OGG1) initiates the base excision repair pathway by removing one ... more 8-Oxoguanine DNA glycosylase 1 (OGG1) initiates the base excision repair pathway by removing one of the most abundant DNA lesions, 8-oxo-7,8-dihydroguanine (8-oxoG). Recent data showed that 8-oxoG not only is a pro-mutagenic genomic base lesion, but also functions as an epigenetic mark and that consequently OGG1 acquire distinct roles in modulation of gene expression. In support, lack of functional OGG1 in Ogg1 mice led to an altered expression of genes including those responsible for the aberrant innate and adaptive immune responses and susceptibility to metabolic disorders. Therefore, the present study examined stimulus-driven OGG1-DNA interactions at whole genome level using chromatin immunoprecipitation (ChIP)-coupled sequencing, and the roles of OGG1 enriched on the genome were validated by molecular and system-level approaches. Results showed that signaling levels of cellular ROS generated by TNFα, induced enrichment of OGG1 at specific sites of chromatinized DNA, primarily in...
A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-ri... more A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-rich clusters; guanines are the bases most susceptible to oxidative modification(s). Consequently, 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the most abundant base lesions in promoters and is primarily repaired via the 8-oxoguanine DNA glycosylase-1 (OOG1)-initiated base excision repair pathway. In view of a prompt cellular response to oxidative challenge, we hypothesized that the 8-oxoG lesion and the cognate repair protein OGG1 are utilized in transcriptional gene activation. Here, we document TNFα-induced enrichment of both 8-oxoG and OGG1 in promoters of pro-inflammatory genes, which precedes interaction of NF-κB with its DNA-binding motif. OGG1 bound to 8-oxoG upstream from the NF-κB motif increased its DNA occupancy by promoting an on-rate of both homodimeric and heterodimeric forms of NF-κB. OGG1 depletion decreased both NF-κB binding and gene expression, whereas Nei-like glycosyl...
Amphotericin B and anidulafungin are widely used antifungal drugs for the treatment of systemic a... more Amphotericin B and anidulafungin are widely used antifungal drugs for the treatment of systemic and serious mycoses.
Journal of immunology (Baltimore, Md. : 1950), 2014
8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanin... more 8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG) via the DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in the genomic DNA leads to genetic instability and carcinogenesis and is thought to contribute to the worsening of various inflammatory and disease processes. However, the disease mechanism is unknown. In this study, we proposed that the mechanistic link between OGG1-BER and proinflammatory gene expression is OGG1's guanine nucleotide exchange factor activity, acquired after interaction with the 8-oxoG base and consequent activation of the small GTPase RAS. To test this hypothesis, we used BALB/c mice expressing or deficient in OGG1 in their airway epithelium and various molecular biological approaches, including active RAS pulldown, reporter and Comet assays, small interfering RNA-mediated depletion of gene expression, quantitative RT-PCR, and immunoblotting. We report that the OGG1-initiated rep...
DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative st... more DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and…
Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base dam... more Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base damage and DNA strand breaks, has a second activity as a transcriptional regulator that binds to several trans -acting factors. APE1 overexpression is often observed in tumor cells and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to such agents. Because the involvement of APE1 in repairing the DNA damage induced by many of these drugs is unlikely, drug resistance may be linked to…
A near-isogenic line (NIL) into which low-molecular-weight glutenin subunits (LMW-GSs) were intro... more A near-isogenic line (NIL) into which low-molecular-weight glutenin subunits (LMW-GSs) were introduced from a Canadian Western Extra-Strong wheat cultivar (Triticum aestivum L.), ‘Glenlea’, into a Japanese spring wheat cultivar, ‘Harunoakebono’, had a much better bread-making quality than does Harunoakebono. LMW-GSs associated with good bread-making quality of the NIL and the allelic LMW-GS in Harunoakebono were monitored by two-dimensional polyacrylamide gel
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