Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (D... more Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of...
With our growing understanding of the pathways involved in cell proliferation and signalling, tar... more With our growing understanding of the pathways involved in cell proliferation and signalling, targeted therapies for the treatment of cancer are entering the clinical arena. New and emerging targets are proteins that participate in DNA repair processes. Inhibition of proteins in these pathways can sensitize cells to DNA damaging agents, such as chemotherapeutics and ionizing radiation, the main tools currently available to improve the outcome of patients with advanced cancers. The efficacy of these treatment methods is directly related to the ability of the agent to specifically induce cytotoxic damage in tumor cells rather than in normal cells. This specific targeting is accomplished through molecular and cellular features of the cancer cell, such as its higher proliferative rate, which may be directly attacked using inhibitors of the cell cycle. Besides compounds that block cell division at the level of mitotic spindle formation (e.g. vinca alkaloids and taxanes), and growth signal inhibitors, which operate through hormonal manipulation by means of therapeutic antibodies or drugs, a growing number of cell cycle inhibitors encompass DNA damaging agents. Genomic damage may cause cell cycle arrest either directly or indirectly as a consequence of abortive DNA replication during the S-phase of the cell cycle. Notably, the ability of cancer cells to efficiently recognize and remove cytotoxic DNA damage plays a key role in therapeutic resistance, thus profoundly affecting therapeutic efficacy [1–3]. Moreover, since some DNA repair pathways are impaired or inactivated in some types of cancers, a detailed comprehension and strategic manipulation of DNA repair mechanisms could improve the efficacy of DNA damage-based anticancer therapies. DNA repair pathways (such as BER, NER, TLS, HR, NHEJ, etc) (Fig. 1) can enable tumor cells to survive DNA damage that is induced by common cancer therapy; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs (Table 1). In addition, alterations in DNA repair pathways that arise during tumour development can make some cancer cells reliant on a reduced set of DNA repair pathways for survival. Indeed, DNA repair pathways are highly interconnected and collaborative, and while a particular DNA lesion can be processed by multiple repair pathways, a single repair process is capable of repairing multiple DNA lesions. Moreover, DNA enzymology, epigenetic regulation and transcriptional regulatory mechanisms need to be highly interconnected and strictly coordinated to guarantee proper relief from the consequences of DNA damage. Therefore, knowledge of the fine-tuning mechanisms able to specifically control the activity of DNA repair enzymes is of the utmost importance both for cancer diagnosis and cancer treatment. Figure 1 Schematic overview of DNA-repair systems and emerging anticancer targets Table 1 List of the known repair pathways involved in repairing toxic DNA lesions induced by most common cancer treatments The present multi author review consists of nine contributions that cover some of the most important aspects of biochemical and functional regulation of key DNA repair enzymes, as well as the current state-of-art strategies to target these proteins in future cancer treatment paradigms. The first paper, by ML Hegde et al., provides a thorough functional and structural overview of the Base Excision Repair (BER) pathway. BER is endowed with the responsibililty of repairing small not-distorting DNA lesions, such as oxidized or aberrant bases and single strand breaks (SSBs), which are produced during cell metabolism or as a consequence of treatment with chemotherapeutic agents (e.g. bleomycin, temozolomide, etc.) [4,5]. Since these lesions are often mutagenic and have etiological linkage to sporadic cancers, the BER pathway is both important in the pathogenesis and treatment of cancer. The contribution by ML Hegde et al. focuses also on a novel structural aspect of the main enzymes in BER, i.e. the DNA glycosylases and apurinic/apyrimidinic (AP) endonuclease, where the disordered segments of these proteins operate as sites of molecular regulation of their activities. A key enzyme in BER is the AP Endonuclease (APE1), which acts as the predominant AP site incision enzyme in mammalian cells. APE1 is a multifunctional ubiquitous and essential protein playing a role both in the pathogenesis of cancer and in resistance to DNA-interactive drugs, such as monofunctional alkylators and antimetabolites. For these reasons, APE1 is acquiring more and more interest as a novel and promising candidate target for anticancer treatment. APE1, which is altered in more aggressive tumors, is a pleiotropic protein playing a critical role not only in DNA repair but also regulating apoptosis, cell proliferation and an adaptive cell response to oxidative stress [6]. These observations, by the way, would be compatible…
Increasing evidence suggests different, not completely understood roles of microRNA biogenesis in... more Increasing evidence suggests different, not completely understood roles of microRNA biogenesis in the development and progression of lung cancer. The overexpression of the DNA repair protein apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is an important cause of poor chemotherapeutic response in lung cancer and its involvement in onco-miRNAs biogenesis has been recently described. Whether APE1 regulates miRNAs acting as prognostic biomarkers of lung cancer has not been investigated, yet. In this study, we analyzed miRNAs differential expression upon APE1 depletion in the A549 lung cancer cell line using high-throughput methods. We defined a signature of 13 miRNAs that strongly correlate with APE1 expression in human lung cancer: miR-1246, miR-4488, miR-24, miR-183, miR-660, miR-130b, miR-543, miR-200c, miR-376c, miR-218, miR-146a, miR-92b and miR-33a. Functional enrichment analysis of this signature revealed its biological relevance in cancer cell proliferation and survival. W...
Liquid-liquid phase separation (LLPS) is a way to concentrate biochemical reactions while excludi... more Liquid-liquid phase separation (LLPS) is a way to concentrate biochemical reactions while excluding noninteracting components. Disordered domains of proteins, as well as interaction with RNA, favor condensation but are not mandatory for modulating this process. Recent insights about phase-separation mechanisms pointed to new fascinating models that could explain how cells could cope with DNA damage responses, conferring both spatial and temporal fine regulation. APE1 is a multifunctional protein belonging to the Base Excision Repair (BER) pathway, bearing additional ‘non-canonical’ DNA-repair functions associated with processes like RNA metabolism. Recently, it has been highlighted that several DNA repair enzymes, such as 53BP1 and APE1, are endowed with RNA binding abilities. In this work, after reviewing the recent literature supporting a role of LLPS in DDR, we analyze, as a proof of principle, the interactome of APE1 using a bioinformatics approach to look for clues of LLPS in B...
Journal of Experimental & Clinical Cancer Research, 2021
Background Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. ... more Background Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon organoids (PDCOs) are a promising 3D-cell model to study tumor identity for personalized medicine, although this approach still lacks detailed characterization regarding molecular stability during culturing conditions. Correlation analysis that considers genomic, transcriptomic, and proteomic data, as well as thawing, timing, and culturing conditions, is missing. Methods Through integrated multi–omics strategies, we characterized PDCOs under different growing and timing conditions, to define their ability to recapitulate the original tumor. Results Whole Exome Sequencing allowed detecting temporal acquisition of somatic variants, in a patient-specific manner, having deleterious effects on ...
APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of ... more APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of DNA lesions and in the transcriptional regulation of genes involved in tumor progression/chemoresistance. Indeed, APE1 overexpression correlates with chemoresistance in more aggressive cancers, and APE1 protein-protein interactions (PPIs) specifically modulate different protein functions in cancer cells. Although important, a detailed investigation on the nature and function of protein interactors regulating APE1 role in tumor progression and chemoresistance is still lacking. The present work was aimed at analyzing the APE1-PPI network with the goal of defining bad prognosis signatures through systematic bioinformatics analysis. By using a well-characterized HeLa cell model stably expressing a flagged APE1 form, which was subjected to extensive proteomics analyses for immunocaptured complexes from different subcellular compartments, we here demonstrate that APE1 is a central hub connecti...
Apurinic/apyrimidinic endonuclease 1 (APE1), the main mammalian AP-endonuclease for the resolutio... more Apurinic/apyrimidinic endonuclease 1 (APE1), the main mammalian AP-endonuclease for the resolution of DNA damages through the base excision repair (BER) pathway, acts as a multifunctional protein in different key cellular processes. The signals to ensure temporo-spatial regulation of APE1 towards a specific function are still a matter of debate. Several studies have suggested that post-translational modifications (PTMs) act as dynamic molecular mechanisms for controlling APE1 functionality. Interestingly, the N-terminal region of APE1 is a disordered portion functioning as an interface for protein binding, as an acceptor site for PTMs and as a target of proteolytic cleavage. We previously demonstrated a cytoplasmic accumulation of truncated APE1 in acute myeloid leukemia (AML) cells in association with a mutated form of nucleophosmin having aberrant cytoplasmic localization (NPM1c+). Here, we mapped the proteolytic sites of APE1 in AML cells at Lys31 and Lys32 and showed that substi...
Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine ki... more Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor-β (TGF-β), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR-TKI responsiveness in NSCLC. The protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR-TKI treatment. The correlation between APE1 expression and progression-free survival (PFS), overall survival (OS), or response rate were analyzed. The impact of APE1 on the response to EGFR-TKIs was measured by exogenous manipulation of APE1 in EGFR-TKI-sensitive and EGFR-TKI-resistant cells. We indicate that low expression of APE1 in tumors is associated with a significantly longer PFS (20.8 months vs 8.4 months, P = 0.008) and a preferential OS (39.0 months vs 17.0 months, P = 0.001), wi...
Mammalian apurinic/apyrimidinic endonuclease 1 is a DNA repair enzyme involved in genome stabilit... more Mammalian apurinic/apyrimidinic endonuclease 1 is a DNA repair enzyme involved in genome stability and expression of genes involved in oxidative stress responses, tumor progression and chemoresistance. However, the molecular mechanisms underlying the role of apurinic/apyrimidinic endonuclease 1 in these processes are still unclear. Recent findings point to a novel role of apurinic/apyrimidinic endonuclease 1 in RNA metabolism. Through the characterization of the interactomes of apurinic/apyrimidinic endonuclease 1 with RNA and other proteins, we demonstrate here a role for apurinic/apyrimidinic endonuclease 1 in pri-miRNA processing and stability via association with the DROSHA-processing complex during genotoxic stress. We also show that endonuclease activity of apurinic/apyrimidinic endonuclease 1 is required for the processing of miR-221/222 in regulating expression of the tumor suppressor PTEN. Analysis of a cohort of different cancers supports the relevance of our findings for ...
Only mammalian apurinic/apyrimidinic endonuclease1 (APE1) has been reported to possess both DNA r... more Only mammalian apurinic/apyrimidinic endonuclease1 (APE1) has been reported to possess both DNA repair and redox activities. C terminal of the protein is required for base excision repair, while the redox activity resides in the N terminal due to cysteine residues at specific positions. APE1s from other organisms studied so far lack the redox activity in spite of having the N terminal domain. We find that APE1 from the Cnidarian Hydra exhibits both endonuclease and redox activities similar to mammalian APE1. We further show the presence of the three indispensable cysteines in Hydra APE1 for redox activity by site directed mutagenesis. Importance of redox domain but not the repair domain of APE1 in regeneration has been demonstrated by using domain-specific inhibitors. Our findings clearly demonstrate that the redox function of APE1 evolved very early in metazoan evolution and is not a recent acquisition in mammalian APE1 as believed so far.
Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (D... more Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of...
With our growing understanding of the pathways involved in cell proliferation and signalling, tar... more With our growing understanding of the pathways involved in cell proliferation and signalling, targeted therapies for the treatment of cancer are entering the clinical arena. New and emerging targets are proteins that participate in DNA repair processes. Inhibition of proteins in these pathways can sensitize cells to DNA damaging agents, such as chemotherapeutics and ionizing radiation, the main tools currently available to improve the outcome of patients with advanced cancers. The efficacy of these treatment methods is directly related to the ability of the agent to specifically induce cytotoxic damage in tumor cells rather than in normal cells. This specific targeting is accomplished through molecular and cellular features of the cancer cell, such as its higher proliferative rate, which may be directly attacked using inhibitors of the cell cycle. Besides compounds that block cell division at the level of mitotic spindle formation (e.g. vinca alkaloids and taxanes), and growth signal inhibitors, which operate through hormonal manipulation by means of therapeutic antibodies or drugs, a growing number of cell cycle inhibitors encompass DNA damaging agents. Genomic damage may cause cell cycle arrest either directly or indirectly as a consequence of abortive DNA replication during the S-phase of the cell cycle. Notably, the ability of cancer cells to efficiently recognize and remove cytotoxic DNA damage plays a key role in therapeutic resistance, thus profoundly affecting therapeutic efficacy [1–3]. Moreover, since some DNA repair pathways are impaired or inactivated in some types of cancers, a detailed comprehension and strategic manipulation of DNA repair mechanisms could improve the efficacy of DNA damage-based anticancer therapies. DNA repair pathways (such as BER, NER, TLS, HR, NHEJ, etc) (Fig. 1) can enable tumor cells to survive DNA damage that is induced by common cancer therapy; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs (Table 1). In addition, alterations in DNA repair pathways that arise during tumour development can make some cancer cells reliant on a reduced set of DNA repair pathways for survival. Indeed, DNA repair pathways are highly interconnected and collaborative, and while a particular DNA lesion can be processed by multiple repair pathways, a single repair process is capable of repairing multiple DNA lesions. Moreover, DNA enzymology, epigenetic regulation and transcriptional regulatory mechanisms need to be highly interconnected and strictly coordinated to guarantee proper relief from the consequences of DNA damage. Therefore, knowledge of the fine-tuning mechanisms able to specifically control the activity of DNA repair enzymes is of the utmost importance both for cancer diagnosis and cancer treatment. Figure 1 Schematic overview of DNA-repair systems and emerging anticancer targets Table 1 List of the known repair pathways involved in repairing toxic DNA lesions induced by most common cancer treatments The present multi author review consists of nine contributions that cover some of the most important aspects of biochemical and functional regulation of key DNA repair enzymes, as well as the current state-of-art strategies to target these proteins in future cancer treatment paradigms. The first paper, by ML Hegde et al., provides a thorough functional and structural overview of the Base Excision Repair (BER) pathway. BER is endowed with the responsibililty of repairing small not-distorting DNA lesions, such as oxidized or aberrant bases and single strand breaks (SSBs), which are produced during cell metabolism or as a consequence of treatment with chemotherapeutic agents (e.g. bleomycin, temozolomide, etc.) [4,5]. Since these lesions are often mutagenic and have etiological linkage to sporadic cancers, the BER pathway is both important in the pathogenesis and treatment of cancer. The contribution by ML Hegde et al. focuses also on a novel structural aspect of the main enzymes in BER, i.e. the DNA glycosylases and apurinic/apyrimidinic (AP) endonuclease, where the disordered segments of these proteins operate as sites of molecular regulation of their activities. A key enzyme in BER is the AP Endonuclease (APE1), which acts as the predominant AP site incision enzyme in mammalian cells. APE1 is a multifunctional ubiquitous and essential protein playing a role both in the pathogenesis of cancer and in resistance to DNA-interactive drugs, such as monofunctional alkylators and antimetabolites. For these reasons, APE1 is acquiring more and more interest as a novel and promising candidate target for anticancer treatment. APE1, which is altered in more aggressive tumors, is a pleiotropic protein playing a critical role not only in DNA repair but also regulating apoptosis, cell proliferation and an adaptive cell response to oxidative stress [6]. These observations, by the way, would be compatible…
Increasing evidence suggests different, not completely understood roles of microRNA biogenesis in... more Increasing evidence suggests different, not completely understood roles of microRNA biogenesis in the development and progression of lung cancer. The overexpression of the DNA repair protein apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is an important cause of poor chemotherapeutic response in lung cancer and its involvement in onco-miRNAs biogenesis has been recently described. Whether APE1 regulates miRNAs acting as prognostic biomarkers of lung cancer has not been investigated, yet. In this study, we analyzed miRNAs differential expression upon APE1 depletion in the A549 lung cancer cell line using high-throughput methods. We defined a signature of 13 miRNAs that strongly correlate with APE1 expression in human lung cancer: miR-1246, miR-4488, miR-24, miR-183, miR-660, miR-130b, miR-543, miR-200c, miR-376c, miR-218, miR-146a, miR-92b and miR-33a. Functional enrichment analysis of this signature revealed its biological relevance in cancer cell proliferation and survival. W...
Liquid-liquid phase separation (LLPS) is a way to concentrate biochemical reactions while excludi... more Liquid-liquid phase separation (LLPS) is a way to concentrate biochemical reactions while excluding noninteracting components. Disordered domains of proteins, as well as interaction with RNA, favor condensation but are not mandatory for modulating this process. Recent insights about phase-separation mechanisms pointed to new fascinating models that could explain how cells could cope with DNA damage responses, conferring both spatial and temporal fine regulation. APE1 is a multifunctional protein belonging to the Base Excision Repair (BER) pathway, bearing additional ‘non-canonical’ DNA-repair functions associated with processes like RNA metabolism. Recently, it has been highlighted that several DNA repair enzymes, such as 53BP1 and APE1, are endowed with RNA binding abilities. In this work, after reviewing the recent literature supporting a role of LLPS in DDR, we analyze, as a proof of principle, the interactome of APE1 using a bioinformatics approach to look for clues of LLPS in B...
Journal of Experimental & Clinical Cancer Research, 2021
Background Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. ... more Background Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon organoids (PDCOs) are a promising 3D-cell model to study tumor identity for personalized medicine, although this approach still lacks detailed characterization regarding molecular stability during culturing conditions. Correlation analysis that considers genomic, transcriptomic, and proteomic data, as well as thawing, timing, and culturing conditions, is missing. Methods Through integrated multi–omics strategies, we characterized PDCOs under different growing and timing conditions, to define their ability to recapitulate the original tumor. Results Whole Exome Sequencing allowed detecting temporal acquisition of somatic variants, in a patient-specific manner, having deleterious effects on ...
APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of ... more APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of DNA lesions and in the transcriptional regulation of genes involved in tumor progression/chemoresistance. Indeed, APE1 overexpression correlates with chemoresistance in more aggressive cancers, and APE1 protein-protein interactions (PPIs) specifically modulate different protein functions in cancer cells. Although important, a detailed investigation on the nature and function of protein interactors regulating APE1 role in tumor progression and chemoresistance is still lacking. The present work was aimed at analyzing the APE1-PPI network with the goal of defining bad prognosis signatures through systematic bioinformatics analysis. By using a well-characterized HeLa cell model stably expressing a flagged APE1 form, which was subjected to extensive proteomics analyses for immunocaptured complexes from different subcellular compartments, we here demonstrate that APE1 is a central hub connecti...
Apurinic/apyrimidinic endonuclease 1 (APE1), the main mammalian AP-endonuclease for the resolutio... more Apurinic/apyrimidinic endonuclease 1 (APE1), the main mammalian AP-endonuclease for the resolution of DNA damages through the base excision repair (BER) pathway, acts as a multifunctional protein in different key cellular processes. The signals to ensure temporo-spatial regulation of APE1 towards a specific function are still a matter of debate. Several studies have suggested that post-translational modifications (PTMs) act as dynamic molecular mechanisms for controlling APE1 functionality. Interestingly, the N-terminal region of APE1 is a disordered portion functioning as an interface for protein binding, as an acceptor site for PTMs and as a target of proteolytic cleavage. We previously demonstrated a cytoplasmic accumulation of truncated APE1 in acute myeloid leukemia (AML) cells in association with a mutated form of nucleophosmin having aberrant cytoplasmic localization (NPM1c+). Here, we mapped the proteolytic sites of APE1 in AML cells at Lys31 and Lys32 and showed that substi...
Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine ki... more Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor-β (TGF-β), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR-TKI responsiveness in NSCLC. The protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR-TKI treatment. The correlation between APE1 expression and progression-free survival (PFS), overall survival (OS), or response rate were analyzed. The impact of APE1 on the response to EGFR-TKIs was measured by exogenous manipulation of APE1 in EGFR-TKI-sensitive and EGFR-TKI-resistant cells. We indicate that low expression of APE1 in tumors is associated with a significantly longer PFS (20.8 months vs 8.4 months, P = 0.008) and a preferential OS (39.0 months vs 17.0 months, P = 0.001), wi...
Mammalian apurinic/apyrimidinic endonuclease 1 is a DNA repair enzyme involved in genome stabilit... more Mammalian apurinic/apyrimidinic endonuclease 1 is a DNA repair enzyme involved in genome stability and expression of genes involved in oxidative stress responses, tumor progression and chemoresistance. However, the molecular mechanisms underlying the role of apurinic/apyrimidinic endonuclease 1 in these processes are still unclear. Recent findings point to a novel role of apurinic/apyrimidinic endonuclease 1 in RNA metabolism. Through the characterization of the interactomes of apurinic/apyrimidinic endonuclease 1 with RNA and other proteins, we demonstrate here a role for apurinic/apyrimidinic endonuclease 1 in pri-miRNA processing and stability via association with the DROSHA-processing complex during genotoxic stress. We also show that endonuclease activity of apurinic/apyrimidinic endonuclease 1 is required for the processing of miR-221/222 in regulating expression of the tumor suppressor PTEN. Analysis of a cohort of different cancers supports the relevance of our findings for ...
Only mammalian apurinic/apyrimidinic endonuclease1 (APE1) has been reported to possess both DNA r... more Only mammalian apurinic/apyrimidinic endonuclease1 (APE1) has been reported to possess both DNA repair and redox activities. C terminal of the protein is required for base excision repair, while the redox activity resides in the N terminal due to cysteine residues at specific positions. APE1s from other organisms studied so far lack the redox activity in spite of having the N terminal domain. We find that APE1 from the Cnidarian Hydra exhibits both endonuclease and redox activities similar to mammalian APE1. We further show the presence of the three indispensable cysteines in Hydra APE1 for redox activity by site directed mutagenesis. Importance of redox domain but not the repair domain of APE1 in regeneration has been demonstrated by using domain-specific inhibitors. Our findings clearly demonstrate that the redox function of APE1 evolved very early in metazoan evolution and is not a recent acquisition in mammalian APE1 as believed so far.
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Papers by Gianluca Tell