Pub Date : 2025-04-03DOI: 10.1016/j.dnarep.2025.103831
Suisui Hao , Zhaojin Liu , Heinz-Josef Lenz , Jian Yu , Lin Zhang
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the United States. A key driver of CRC development is microsatellite instability (MSI), which is caused by DNA mismatch repair deficiency and characterized by hypermutability of short-tandem repeat sequences. A significant portion of MSI CRCs do not respond to checkpoint immunotherapy treatments, highlighting an unmet need for improved therapies. Recent studies have revealed that MSI cancer cells require Werner (WRN), a RecQ family DNA helicase, for survival. Inhibiting WRN has emerged as a promising approach for targeting MSI CRCs that are insensitive to standard therapies. Several highly potent small-molecule WRN inhibitors have been developed and exhibited striking in vitro and in vivo activities against MSI cancers. Two of these WRN inhibitors, HRO761 and VVD-133214, have recently entered clinical trials. In this review, we summarize recent studies on WRN as a synthetic lethal target in MSI CRC and the development of WRN inhibitors as a new class of anticancer agents.
{"title":"Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer","authors":"Suisui Hao , Zhaojin Liu , Heinz-Josef Lenz , Jian Yu , Lin Zhang","doi":"10.1016/j.dnarep.2025.103831","DOIUrl":"10.1016/j.dnarep.2025.103831","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the United States. A key driver of CRC development is microsatellite instability (MSI), which is caused by DNA mismatch repair deficiency and characterized by hypermutability of short-tandem repeat sequences. A significant portion of MSI CRCs do not respond to checkpoint immunotherapy treatments, highlighting an unmet need for improved therapies. Recent studies have revealed that MSI cancer cells require Werner (WRN), a RecQ family DNA helicase, for survival. Inhibiting WRN has emerged as a promising approach for targeting MSI CRCs that are insensitive to standard therapies. Several highly potent small-molecule WRN inhibitors have been developed and exhibited striking <em>in vitro</em> and <em>in vivo</em> activities against MSI cancers. Two of these WRN inhibitors, HRO761 and VVD-133214, have recently entered clinical trials. In this review, we summarize recent studies on WRN as a synthetic lethal target in MSI CRC and the development of WRN inhibitors as a new class of anticancer agents.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103831"},"PeriodicalIF":3.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-23DOI: 10.1016/j.dnarep.2025.103828
Marcos R.M. Fontes , Fábio F. Cardoso , Bostjan Kobe
DNA repair is a crucial biological process necessary to address damage caused by both endogenous and exogenous agents, with at least five major pathways recognized as central to this process. In several cancer types and other diseases, including neurodegenerative disorders, DNA repair mechanisms are often disrupted or dysregulated. Despite the diversity of these proteins and their roles, they all share the common requirement of being imported into the cell nucleus to perform their functions. Therefore, understanding the nuclear import of these proteins is essential for comprehending their roles in cellular processes. The first and best-characterized nuclear targeting signal is the classical nuclear localization sequence (NLS), recognized by importin-α (Impα). Several structural and affinity studies have been conducted on complexes formed between Impα and NLSs from DNA repair proteins, although these represent only a fraction of all known DNA repair proteins. These studies have significantly advanced our understanding of the nuclear import process of DNA repair proteins, often revealing unexpected results that challenge existing literature and computational predictions. Despite advances in computational, biochemical, and cellular assays, structural methods – particularly crystallography and in-solution biophysical approaches – continue to play a critical role in providing insights into molecular events operating in biological pathways. In this review, we aim to summarize experimental structural and affinity studies involving Impα and NLSs from DNA repair proteins, with the goal of furthering our understanding of the function of these essential proteins.
{"title":"Transport of DNA repair proteins to the cell nucleus by the classical nuclear importin pathway – a structural overview","authors":"Marcos R.M. Fontes , Fábio F. Cardoso , Bostjan Kobe","doi":"10.1016/j.dnarep.2025.103828","DOIUrl":"10.1016/j.dnarep.2025.103828","url":null,"abstract":"<div><div>DNA repair is a crucial biological process necessary to address damage caused by both endogenous and exogenous agents, with at least five major pathways recognized as central to this process. In several cancer types and other diseases, including neurodegenerative disorders, DNA repair mechanisms are often disrupted or dysregulated. Despite the diversity of these proteins and their roles, they all share the common requirement of being imported into the cell nucleus to perform their functions. Therefore, understanding the nuclear import of these proteins is essential for comprehending their roles in cellular processes. The first and best-characterized nuclear targeting signal is the classical nuclear localization sequence (NLS), recognized by importin-α (Impα). Several structural and affinity studies have been conducted on complexes formed between Impα and NLSs from DNA repair proteins, although these represent only a fraction of all known DNA repair proteins. These studies have significantly advanced our understanding of the nuclear import process of DNA repair proteins, often revealing unexpected results that challenge existing literature and computational predictions. Despite advances in computational, biochemical, and cellular assays, structural methods – particularly crystallography and in-solution biophysical approaches – continue to play a critical role in providing insights into molecular events operating in biological pathways. In this review, we aim to summarize experimental structural and affinity studies involving Impα and NLSs from DNA repair proteins, with the goal of furthering our understanding of the function of these essential proteins.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103828"},"PeriodicalIF":3.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143714593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-16DOI: 10.1016/j.dnarep.2025.103827
Xavier Renaudin , Anna Campalans
Oxidative DNA damage, resulting from endogenous cellular processes and external sources plays a significant role in mutagenesis, cancer progression, and the pathogenesis of neurological disorders. Base Excision Repair (BER) is involved in the repair of base modifications such as oxidations or alkylations as well as single strand breaks. The DNA glycosylase OGG1, initiates the BER pathway by the recognition and excision of 8oxoG, the most common oxidative DNA lesion, in both nuclear and mitochondrial DNA. Beyond DNA repair, OGG1 modulates transcription, particularly pro-inflammatory genes, linking oxidative DNA damage to broader biological processes like inflammation and aging. In cancer therapy, BER inhibition has emerged as a promising strategy to enhance treatment efficacy. Targeting OGG1 sensitizes cells to chemotherapies, radiotherapies, and PARP inhibitors, presenting opportunities to overcome therapy resistance. Additionally, OGG1 activators hold potential in mitigating oxidative damage associated with aging and neurological disorders. This review presents the development of several inhibitors and activators of OGG1 and how they have contributed to advance our knowledge in the fundamental functions of OGG1. We also discuss the new opportunities they provide for clinical applications in treating cancer, inflammation and neurological disorders. Finally, we also highlight the challenges in targeting OGG1, particularly regarding the off-target effects recently reported for some inhibitors and how we can overcome these limitations.
{"title":"Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges","authors":"Xavier Renaudin , Anna Campalans","doi":"10.1016/j.dnarep.2025.103827","DOIUrl":"10.1016/j.dnarep.2025.103827","url":null,"abstract":"<div><div>Oxidative DNA damage, resulting from endogenous cellular processes and external sources plays a significant role in mutagenesis, cancer progression, and the pathogenesis of neurological disorders. Base Excision Repair (BER) is involved in the repair of base modifications such as oxidations or alkylations as well as single strand breaks. The DNA glycosylase OGG1, initiates the BER pathway by the recognition and excision of 8oxoG, the most common oxidative DNA lesion, in both nuclear and mitochondrial DNA. Beyond DNA repair, OGG1 modulates transcription, particularly pro-inflammatory genes, linking oxidative DNA damage to broader biological processes like inflammation and aging. In cancer therapy, BER inhibition has emerged as a promising strategy to enhance treatment efficacy. Targeting OGG1 sensitizes cells to chemotherapies, radiotherapies, and PARP inhibitors, presenting opportunities to overcome therapy resistance. Additionally, OGG1 activators hold potential in mitigating oxidative damage associated with aging and neurological disorders. This review presents the development of several inhibitors and activators of OGG1 and how they have contributed to advance our knowledge in the fundamental functions of OGG1. We also discuss the new opportunities they provide for clinical applications in treating cancer, inflammation and neurological disorders. Finally, we also highlight the challenges in targeting OGG1, particularly regarding the off-target effects recently reported for some inhibitors and how we can overcome these limitations.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103827"},"PeriodicalIF":3.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-13DOI: 10.1016/j.dnarep.2025.103825
Junyi Chen , Wenkang Zhang , Yuqi Ma , Xueqing Yan , Yugang Wang , Qi Ouyang , Min Wu , Gen Yang
Over the past two decades, there has been intense debate regarding whether DNA double-strand breaks (DSBs) maintain a relatively stable position or cluster in mammalian cells. The clustering of DSB and its spatiotemporal properties remain unclear. Here, we provided evidence supporting DSB clustering, using laser microirradiation to induce high-precision damage in cells. The probability of 53BP1 foci clustering varies with the distance between them. 53BP1 foci clustering occurs during the early phase of DNA damage response (DDR) and the repair phase, but not during the repair plateau phase. The clustering at different phases has distinct implications for DNA repair. Clustering accelerates the DSB repair process. These results demonstrate that the extent of 53BP1 foci clustering is influenced by both temporal and spatial factors. Such findings could enhance our understanding of the mechanism of DSB clustering and the DDR, ultimately contributing to the development of improved DNA repair therapies for various diseases.
{"title":"Temporal and spatial dynamics of DNA double-strand break repair centers","authors":"Junyi Chen , Wenkang Zhang , Yuqi Ma , Xueqing Yan , Yugang Wang , Qi Ouyang , Min Wu , Gen Yang","doi":"10.1016/j.dnarep.2025.103825","DOIUrl":"10.1016/j.dnarep.2025.103825","url":null,"abstract":"<div><div>Over the past two decades, there has been intense debate regarding whether DNA double-strand breaks (DSBs) maintain a relatively stable position or cluster in mammalian cells. The clustering of DSB and its spatiotemporal properties remain unclear. Here, we provided evidence supporting DSB clustering, using laser microirradiation to induce high-precision damage in cells. The probability of 53BP1 foci clustering varies with the distance between them. 53BP1 foci clustering occurs during the early phase of DNA damage response (DDR) and the repair phase, but not during the repair plateau phase. The clustering at different phases has distinct implications for DNA repair. Clustering accelerates the DSB repair process. These results demonstrate that the extent of 53BP1 foci clustering is influenced by both temporal and spatial factors. Such findings could enhance our understanding of the mechanism of DSB clustering and the DDR, ultimately contributing to the development of improved DNA repair therapies for various diseases.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103825"},"PeriodicalIF":3.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-10DOI: 10.1016/j.dnarep.2025.103826
Melike Çağlayan
Base excision repair (BER) is the critical mechanism for preventing mutagenic and lethal consequences of single base lesions generated by endogenous factors or exposure to environmental hazards. BER pathway involves multi-step enzymatic reactions that require a tight coordination between repair proteins to transfer DNA intermediates in an orderly manner. Though often considered an accurate process, the BER can contribute to genome instability if normal coordination between gap filling by DNA polymerase (pol) β and subsequent nick sealing by DNA ligase 1 (LIG1) or DNA ligase 3α (LIG3α) breaks down at the downstream steps. Our studies demonstrated that an inaccurate DNA ligation by LIG1/LIG3α, stemming from an uncoordinated repair with polβ, leads to a range of deviations from canonical BER pathway, faulty repair events, and formation of deleterious DNA intermediates. Furthermore, X-ray repair cross-complementing protein 1 (XRCC1), as a scaffolding factor, enhances the processivity of downstream steps, and the DNA-end processing enzymes, Aprataxin (APTX), Flap-Endonuclease 1 (FEN1), and AP-Endonuclease 1 (APE1), play critical roles for cleaning of ligase failure products and proofreading of polβ errors in coordination with BER ligases. Overall, our studies contribute to understanding of how a multi-protein repair complex interplay at the final steps to maintain the repair efficiency.
{"title":"Repair pathway coordination from gap filling by polβ and subsequent nick sealing by LIG1 or LIG3α governs BER efficiency at the downstream steps","authors":"Melike Çağlayan","doi":"10.1016/j.dnarep.2025.103826","DOIUrl":"10.1016/j.dnarep.2025.103826","url":null,"abstract":"<div><div>Base excision repair (BER) is the critical mechanism for preventing mutagenic and lethal consequences of single base lesions generated by endogenous factors or exposure to environmental hazards. BER pathway involves multi-step enzymatic reactions that require a tight coordination between repair proteins to transfer DNA intermediates in an orderly manner. Though often considered an accurate process, the BER can contribute to genome instability if normal coordination between gap filling by DNA polymerase (pol) β and subsequent nick sealing by DNA ligase 1 (LIG1) or DNA ligase 3α (LIG3α) breaks down at the downstream steps. Our studies demonstrated that an inaccurate DNA ligation by LIG1/LIG3α, stemming from an uncoordinated repair with polβ, leads to a range of deviations from canonical BER pathway, faulty repair events, and formation of deleterious DNA intermediates. Furthermore, X-ray repair cross-complementing protein 1 (XRCC1), as a scaffolding factor, enhances the processivity of downstream steps, and the DNA-end processing enzymes, Aprataxin (APTX), Flap-Endonuclease 1 (FEN1), and AP-Endonuclease 1 (APE1), play critical roles for cleaning of ligase failure products and proofreading of polβ errors in coordination with BER ligases. Overall, our studies contribute to understanding of how a multi-protein repair complex interplay at the final steps to maintain the repair efficiency.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"148 ","pages":"Article 103826"},"PeriodicalIF":3.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1016/j.dnarep.2025.103824
Peng Li , Duo Wu , Xiaochun Yu
Poly(ADP-ribosyl)ation (PARylation), a reversible post-translational modification mediated by poly(ADP-ribose) polymerases (PARPs), plays crucial roles in DNA replication and DNA damage repair. Since interfering PARylation induces selective cytotoxicity in tumor cells with homologous recombination defects, PARP inhibitors (PARPi) have significant clinical impacts in treating BRCA-mutant cancer patients. Likewise, dePARylation is also essential for optimal DNA damage response and genomic stability. This process is mediated by a group of dePARylation enzymes, such as poly(ADP-ribose) glycohydrolase (PARG). Currently, several novel PARG inhibitors have been developed and examined in preclinical and clinical studies, demonstrating promising anti-cancer activity distinct from PARP inhibitors. This review discusses the role of dePARylation in genome stability and the potential of PARG inhibitors in cancer therapy.
{"title":"Targeting dePARylation in cancer therapy","authors":"Peng Li , Duo Wu , Xiaochun Yu","doi":"10.1016/j.dnarep.2025.103824","DOIUrl":"10.1016/j.dnarep.2025.103824","url":null,"abstract":"<div><div>Poly(ADP-ribosyl)ation (PARylation), a reversible post-translational modification mediated by poly(ADP-ribose) polymerases (PARPs), plays crucial roles in DNA replication and DNA damage repair. Since interfering PARylation induces selective cytotoxicity in tumor cells with homologous recombination defects, PARP inhibitors (PARPi) have significant clinical impacts in treating BRCA-mutant cancer patients. Likewise, dePARylation is also essential for optimal DNA damage response and genomic stability. This process is mediated by a group of dePARylation enzymes, such as poly(ADP-ribose) glycohydrolase (PARG). Currently, several novel PARG inhibitors have been developed and examined in preclinical and clinical studies, demonstrating promising anti-cancer activity distinct from PARP inhibitors. This review discusses the role of dePARylation in genome stability and the potential of PARG inhibitors in cancer therapy.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"148 ","pages":"Article 103824"},"PeriodicalIF":3.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.dnarep.2025.103822
JT DeWitt , D. Jimenez-Tovar , A. Mazumder , S. Haricharan
Mismatch repair (MMR) is a highly conserved, fundamental DNA damage repair pathway that maintains genomic fidelity during cell replication. MMR dysregulation contributes to tumor formation by promoting genomic instability thereby increasing the frequency of potentially oncogenic mutational events. Therefore, MMR dysregulation, in its tumor suppressor role, is largely studied in the context of genomic instability and associated response to immune checkpoint blockade therapies. However, a growing body of literature suggests that the impact of MMR dysregulation on tumor phenotypes is more nuanced than a concerted impact on genomic stability. Rather, loss of individual MMR genes promotes distinct cancer-relevant biological phenotypes, and these phenotypes are further modulated by the tissue of tumor origin. Here, we explore relevant literature and review the prognostic and predictive significance of these non-canonical discoveries.
{"title":"Advances in diagnostic and therapeutic applications of mismatch repair loss in cancer","authors":"JT DeWitt , D. Jimenez-Tovar , A. Mazumder , S. Haricharan","doi":"10.1016/j.dnarep.2025.103822","DOIUrl":"10.1016/j.dnarep.2025.103822","url":null,"abstract":"<div><div>Mismatch repair (MMR) is a highly conserved, fundamental DNA damage repair pathway that maintains genomic fidelity during cell replication. MMR dysregulation contributes to tumor formation by promoting genomic instability thereby increasing the frequency of potentially oncogenic mutational events. Therefore, MMR dysregulation, in its tumor suppressor role, is largely studied in the context of genomic instability and associated response to immune checkpoint blockade therapies. However, a growing body of literature suggests that the impact of MMR dysregulation on tumor phenotypes is more nuanced than a concerted impact on genomic stability. Rather, loss of individual MMR genes promotes distinct cancer-relevant biological phenotypes, and these phenotypes are further modulated by the tissue of tumor origin. Here, we explore relevant literature and review the prognostic and predictive significance of these non-canonical discoveries.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"147 ","pages":"Article 103822"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.dnarep.2025.103821
Mustapha Olatunji , Yuan Liu
Endogenous and environmental stressors can damage DNA and RNA to compromise genome and transcriptome stability and integrity in cells, leading to genetic instability and diseases. Recent studies have demonstrated that RNA damage can also modulate genome stability via RNA-templated DNA synthesis, suggesting that it is essential to maintain RNA integrity for the sustainment of genome stability. However, little is known about RNA damage and repair and their roles in modulating genome stability. Current efforts have mainly focused on revealing RNA surveillance pathways that detect and degrade damaged RNA, while the critical role of RNA repair is often overlooked. Due to their abundance and susceptibility to nucleobase damaging agents, it is essential for cells to evolve robust RNA repair mechanisms that can remove RNA damage, maintaining RNA integrity during gene transcription. This is supported by the discovery of the alkylated RNA nucleobase repair enzyme human AlkB homolog 3 that can directly remove the methyl group on damaged RNA nucleobases, predominantly in the nucleus of human cells, thereby restoring the integrity of the damaged RNA nucleobases. This is further supported by the fact that several DNA repair enzymes can also process RNA damage. In this review, we discuss RNA damage and its effects on cellular function, DNA repair, genome instability, and potential RNA damage repair mechanisms. Our review underscores the necessity for future research on RNA damage and repair and their essential roles in modulating genome stability.
{"title":"RNA damage and its implications in genome stability","authors":"Mustapha Olatunji , Yuan Liu","doi":"10.1016/j.dnarep.2025.103821","DOIUrl":"10.1016/j.dnarep.2025.103821","url":null,"abstract":"<div><div>Endogenous and environmental stressors can damage DNA and RNA to compromise genome and transcriptome stability and integrity in cells, leading to genetic instability and diseases. Recent studies have demonstrated that RNA damage can also modulate genome stability via RNA-templated DNA synthesis, suggesting that it is essential to maintain RNA integrity for the sustainment of genome stability. However, little is known about RNA damage and repair and their roles in modulating genome stability. Current efforts have mainly focused on revealing RNA surveillance pathways that detect and degrade damaged RNA, while the critical role of RNA repair is often overlooked. Due to their abundance and susceptibility to nucleobase damaging agents, it is essential for cells to evolve robust RNA repair mechanisms that can remove RNA damage, maintaining RNA integrity during gene transcription. This is supported by the discovery of the alkylated RNA nucleobase repair enzyme human AlkB homolog 3 that can directly remove the methyl group on damaged RNA nucleobases, predominantly in the nucleus of human cells, thereby restoring the integrity of the damaged RNA nucleobases. This is further supported by the fact that several DNA repair enzymes can also process RNA damage. In this review, we discuss RNA damage and its effects on cellular function, DNA repair, genome instability, and potential RNA damage repair mechanisms. Our review underscores the necessity for future research on RNA damage and repair and their essential roles in modulating genome stability.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"147 ","pages":"Article 103821"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-28DOI: 10.1016/j.dnarep.2025.103823
Anna V. Yudkina , Dmitry O. Zharkov
Abasic, or apurinic/apyrimidinic sites (AP sites) are among the most abundant DNA lesions, appearing in DNA both through spontaneous base loss and as intermediates of base excision DNA repair. Natural aldehydic AP sites have been known for decades and their interaction with the cellular replication, transcription and repair machinery has been investigated in detail. Oxidized AP sites, produced by free radical attack on intact nucleotides, received much attention recently due to their ability to trap DNA repair enzymes and chromatin structural proteins such as histones. In the past few years, it became clear that the reactive nature of aldehydic and oxidized AP sites produces a variety of modifications, including AP site–protein and AP site–peptide cross-links, adducts with small molecules of metabolic or xenobiotic origin, and AP site-mediated interstrand DNA cross-links. The diverse chemical nature of these common-origin lesions is reflected in the wide range of their biological consequences. In this review, we summarize the data on the mechanisms of modified AP sites generation, their abundance, the ability to block DNA polymerases or cause nucleotide misincorporation, and the pathways of their repair.
{"title":"The hidden elephant: Modified abasic sites and their consequences","authors":"Anna V. Yudkina , Dmitry O. Zharkov","doi":"10.1016/j.dnarep.2025.103823","DOIUrl":"10.1016/j.dnarep.2025.103823","url":null,"abstract":"<div><div>Abasic, or apurinic/apyrimidinic sites (AP sites) are among the most abundant DNA lesions, appearing in DNA both through spontaneous base loss and as intermediates of base excision DNA repair. Natural aldehydic AP sites have been known for decades and their interaction with the cellular replication, transcription and repair machinery has been investigated in detail. Oxidized AP sites, produced by free radical attack on intact nucleotides, received much attention recently due to their ability to trap DNA repair enzymes and chromatin structural proteins such as histones. In the past few years, it became clear that the reactive nature of aldehydic and oxidized AP sites produces a variety of modifications, including AP site–protein and AP site–peptide cross-links, adducts with small molecules of metabolic or xenobiotic origin, and AP site-mediated interstrand DNA cross-links. The diverse chemical nature of these common-origin lesions is reflected in the wide range of their biological consequences. In this review, we summarize the data on the mechanisms of modified AP sites generation, their abundance, the ability to block DNA polymerases or cause nucleotide misincorporation, and the pathways of their repair.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"148 ","pages":"Article 103823"},"PeriodicalIF":3.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号