Pub Date : 2025-06-24DOI: 10.1016/j.dnarep.2025.103863
Joséphine Groslambert , Kira Schützenhofer , Luca Palazzo , Ivan Ahel
The PARP family of enzymes catalyzes ADP-ribosylation, a modification of macromolecules, and plays a crucial role in DNA damage repair. The landmark discovery that cancer cells deficient in homologous recombination repair are highly sensitive to PARP inhibitors has paved the way for the clinical success of multiple PARP inhibitors in the treatment of breast, ovarian, pancreatic, and prostate cancers. This clinical success has spurred interest in targeting additional regulators of ADP-ribosylation, with the ADP-ribosyl hydrolase PARG emerging as a promising therapeutic target. Pre-clinical studies have revealed that PARG inhibitors amplify and exploit replication-associated defects, offering a therapeutic window distinct from that of PARP inhibitors. This review provides an overview of the physiological functions of PARPs and PARG, examines the molecular and cellular effects of their inhibitors, and discusses their clinical applications. Finally, we explore the potential of other ADP-ribosylation regulators as novel cancer biomarkers.
{"title":"PARPs and ADP-ribosyl hydrolases in cancer therapy: From drug targets to biomarkers","authors":"Joséphine Groslambert , Kira Schützenhofer , Luca Palazzo , Ivan Ahel","doi":"10.1016/j.dnarep.2025.103863","DOIUrl":"10.1016/j.dnarep.2025.103863","url":null,"abstract":"<div><div>The PARP family of enzymes catalyzes ADP-ribosylation, a modification of macromolecules, and plays a crucial role in DNA damage repair. The landmark discovery that cancer cells deficient in homologous recombination repair are highly sensitive to PARP inhibitors has paved the way for the clinical success of multiple PARP inhibitors in the treatment of breast, ovarian, pancreatic, and prostate cancers. This clinical success has spurred interest in targeting additional regulators of ADP-ribosylation, with the ADP-ribosyl hydrolase PARG emerging as a promising therapeutic target. Pre-clinical studies have revealed that PARG inhibitors amplify and exploit replication-associated defects, offering a therapeutic window distinct from that of PARP inhibitors. This review provides an overview of the physiological functions of PARPs and PARG, examines the molecular and cellular effects of their inhibitors, and discusses their clinical applications. Finally, we explore the potential of other ADP-ribosylation regulators as novel cancer biomarkers.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103863"},"PeriodicalIF":3.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501017","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 : 2025-06-23DOI: 10.1016/j.dnarep.2025.103864
Hui-Lan Chang , Kang-Yi Su , Steven D. Goodman , Yung-Chu Chuang , Shen-Jyue Hsu , Yi-Kai Fang , Hsiao-Pei Yu , Cheng-Hao Fang , Ya-Chien Yang , Sui-Yuan Chang , Woei-horng Fang
Escherichia coli DNA polymerase I (Pol I) possesses a 3’ to 5’ proofreading function. Using a non-inhibitory in vitro proofreading assay and MALDI-TOF MS analysis, we demonstrated the Pol I proofreading function was effective at removal of mismatches within the primer-template junction. Mismatches of 1–4 nucleotides (nt) from the primer 3′ end could be completely or partially corrected, with no additional editing observed further upstream. A backward movement mechanism was proposed involving distributive backtracking of polymerase along the template to remove non-fully complemented primers in order for DNA synthesis to recover. Co-editing DNA substrates containing two mismatches, one at 1–4-nt of the primer 3’ end and the other outside of normal proofreading range, confirmed our distributive backtracking hypothesis. Additionally, a time course analysis revealed proofreading of internal mismatches was a non-processive reaction. To further confirm the validity of our proofreading model, we used in vivo, phagemid-derived nicked C-C substrates. Transformation results were consistent with the notion that mismatches located less than 4-nt upstream of the 3′ end could be successfully proofread. In vivo proofreading of double mismatches also supports our model of polymerase backtracking for internal mismatch editing.
{"title":"Proofreading of mismatches within primer-template junctions by Escherichia coli DNA polymerase I in vitro and in vivo","authors":"Hui-Lan Chang , Kang-Yi Su , Steven D. Goodman , Yung-Chu Chuang , Shen-Jyue Hsu , Yi-Kai Fang , Hsiao-Pei Yu , Cheng-Hao Fang , Ya-Chien Yang , Sui-Yuan Chang , Woei-horng Fang","doi":"10.1016/j.dnarep.2025.103864","DOIUrl":"10.1016/j.dnarep.2025.103864","url":null,"abstract":"<div><div><em>Escherichia coli</em> DNA polymerase I (Pol I) possesses a 3’ to 5’ proofreading function. Using a non-inhibitory <em>in vitro</em> proofreading assay and MALDI-TOF MS analysis, we demonstrated the Pol I proofreading function was effective at removal of mismatches within the primer-template junction. Mismatches of 1–4 nucleotides (nt) from the primer 3′ end could be completely or partially corrected, with no additional editing observed further upstream. A backward movement mechanism was proposed involving distributive backtracking of polymerase along the template to remove non-fully complemented primers in order for DNA synthesis to recover. Co-editing DNA substrates containing two mismatches, one at 1–4-nt of the primer 3’ end and the other outside of normal proofreading range, confirmed our distributive backtracking hypothesis. Additionally, a time course analysis revealed proofreading of internal mismatches was a non-processive reaction. To further confirm the validity of our proofreading model, we used <em>in vivo</em>, phagemid-derived nicked C-C substrates. Transformation results were consistent with the notion that mismatches located less than 4-nt upstream of the 3′ end could be successfully proofread. <em>In vivo</em> proofreading of double mismatches also supports our model of polymerase backtracking for internal mismatch editing.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103864"},"PeriodicalIF":3.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488960","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}
Cockayne syndrome (CS) is a disorder characterized by neurodegeneration and a segmental progeroid phenotype, resulting from mutations in ERCC8/CSA or ERCC6/CSB genes. These genes encode proteins essential for the DNA repair pathway known as transcription-coupled nucleotide excision repair (TC-NER). To further investigate the biological pathways associated with this phenotype, we analyzed transcriptome datasets specific to CS. We conducted RNA-seq on the Csa-/- mouse model at three different age timepoints, and re-analyzed 8 microarray- or RNA-seq based CS transcriptomes present in Gene Expression Omnibus that contained appropriate isogenic controls. We identified differentially expressed genes in each dataset, which were subsequently used for pathway enrichment analysis. Our findings revealed that gene expression of CCL2 and VCAN was altered in the majority of the CS transcriptomes analyzed. Over-representation enrichment analyses of human CS transcriptomes revealed significant changes in genes related to the MAPK, ERK1/2, PI3K-Akt pathways, alongside pathways related to neuronal processes and extracellular matrix metabolism. Additionally, gene-set enrichment analysis of nervous tissue CS datasets highlighted terms related to inflammation and synapse biology. These pathways and processes may contribute to the neurological dysfunction and overall phenotype of CS, presenting promising avenues for future research into the etiology and potential treatments for this aging-related disorder.
{"title":"Altered pathways in Cockayne syndrome: Involvement of MAPK, PI3K-Akt, extracellular matrix, inflammation, and neuronal signaling","authors":"Gustavo Satoru Kajitani , Marina Andrade Tomaz , Giovana da Silva Leandro , Carolina Quayle , Lorrana Cachuite Mendes Rocha , Tiago Antonio de Souza , Leandro Márcio Moreira , Izinara Rosse , Carlos Frederico Martins Menck , Camila Carrião Machado Garcia","doi":"10.1016/j.dnarep.2025.103861","DOIUrl":"10.1016/j.dnarep.2025.103861","url":null,"abstract":"<div><div>Cockayne syndrome (CS) is a disorder characterized by neurodegeneration and a segmental progeroid phenotype, resulting from mutations in <em>ERCC8/CSA</em> or <em>ERCC6/CSB</em> genes. These genes encode proteins essential for the DNA repair pathway known as transcription-coupled nucleotide excision repair (TC-NER). To further investigate the biological pathways associated with this phenotype, we analyzed transcriptome datasets specific to CS. We conducted RNA-seq on the Csa<sup>-/-</sup> mouse model at three different age timepoints, and re-analyzed 8 microarray- or RNA-seq based CS transcriptomes present in Gene Expression Omnibus that contained appropriate isogenic controls. We identified differentially expressed genes in each dataset, which were subsequently used for pathway enrichment analysis. Our findings revealed that gene expression of <em>CCL2</em> and <em>VCAN</em> was altered in the majority of the CS transcriptomes analyzed. Over-representation enrichment analyses of human CS transcriptomes revealed significant changes in genes related to the MAPK, ERK1/2, PI3K-Akt pathways, alongside pathways related to neuronal processes and extracellular matrix metabolism. Additionally, gene-set enrichment analysis of nervous tissue CS datasets highlighted terms related to inflammation and synapse biology. These pathways and processes may contribute to the neurological dysfunction and overall phenotype of CS, presenting promising avenues for future research into the etiology and potential treatments for this aging-related disorder.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103861"},"PeriodicalIF":3.0,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144480710","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 : 2025-06-17DOI: 10.1016/j.dnarep.2025.103860
Yisui Xia , Zhao-Qi Wang , Xingzhi Xu
The 20th Ataxia-Telangiectasia Workshop (ATW-2024) in conjunction with the 15th International Symposium on DNA Damage Response & Human Disease (isDDRHD-2024) was held in Shenzhen, China, on October 17–20th, 2024. Organized by Xingzhi Xu, Zhao-Qi Wang, and Peter McKinnon, the conference gathered global experts to advance discussions on Ataxia-Telangiectasia research, DNA damage response, genome stability, and cancer. The event featured 2 keynote speeches, 52 invited talks, and 24 poster presentations, divided into 12 sessions. The meeting fostered rich discussions among established and junior scientists, including students coming from 14 countries in the world. The meeting topics include basic and clinical research deciphering the aetiology of A-T and related genomic instability disorders.
{"title":"DNA damage response and genomic instability disorder: Meeting report of the 20th Ataxia-Telangiectasia Workshop (ATW-2024) in conjunction with the 15th international symposium on DNA damage response & human disease (isDDRHD-2024)","authors":"Yisui Xia , Zhao-Qi Wang , Xingzhi Xu","doi":"10.1016/j.dnarep.2025.103860","DOIUrl":"10.1016/j.dnarep.2025.103860","url":null,"abstract":"<div><div>The 20<sup>th</sup> Ataxia-Telangiectasia Workshop (ATW-2024) in conjunction with the 15<sup>th</sup> International Symposium on DNA Damage Response & Human Disease (isDDRHD-2024) was held in Shenzhen, China, on October 17–20<sup>th</sup>, 2024. Organized by Xingzhi Xu, Zhao-Qi Wang, and Peter McKinnon, the conference gathered global experts to advance discussions on Ataxia-Telangiectasia research, DNA damage response, genome stability, and cancer. The event featured 2 keynote speeches, 52 invited talks, and 24 poster presentations, divided into 12 sessions. The meeting fostered rich discussions among established and junior scientists, including students coming from 14 countries in the world. The meeting topics include basic and clinical research deciphering the aetiology of A-T and related genomic instability disorders.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103860"},"PeriodicalIF":3.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144480711","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 : 2025-06-13DOI: 10.1016/j.dnarep.2025.103857
Hongxiu Liu , Zhihua Li , Yihua Wang , Can Li , Kaiqing Yan , Yanping Ma
Genomic rearrangements and instability are key pathological features of multiple myeloma (MM). However, the origins of DNA damage in MM and its impact on disease progression remain incompletely understood. Here, we screened DNA damage repair (DDR) genes from single-cell RNA sequencing and bulkRNA-seq datasets using WGCNA and differential expression analysis. A prognostic model was constructed, demonstrating that patients in high DDR expression group had poor outcomes in both the training and validation cohorts. The nomogram also indicated that DDR-related risk scores had good predictive performance. Then, the differences of immune infiltration and mutation landscape between low and high DDR group were investigated. PARP1, PCNA, and RAD23A were identified as key DDR-related genes in MM. Additionally, we explored the drug sensitivity and potential molecular mechanisms associated with each key gene. Altogether, the DDR-related prognostic risk model in MM may facilitate risk stratification and guide treatment decisions, with key prognostic genes might potentially serving as biomarkers and therapeutic targets.
{"title":"DNA damage repair (DDR) related prognostic risk model in multiple myeloma based on single-cell and bulk sequencing","authors":"Hongxiu Liu , Zhihua Li , Yihua Wang , Can Li , Kaiqing Yan , Yanping Ma","doi":"10.1016/j.dnarep.2025.103857","DOIUrl":"10.1016/j.dnarep.2025.103857","url":null,"abstract":"<div><div>Genomic rearrangements and instability are key pathological features of multiple myeloma (MM). However, the origins of DNA damage in MM and its impact on disease progression remain incompletely understood. Here, we screened DNA damage repair (DDR) genes from single-cell RNA sequencing and bulkRNA-seq datasets using WGCNA and differential expression analysis. A prognostic model was constructed, demonstrating that patients in high DDR expression group had poor outcomes in both the training and validation cohorts. The nomogram also indicated that DDR-related risk scores had good predictive performance. Then, the differences of immune infiltration and mutation landscape between low and high DDR group were investigated. PARP1, PCNA, and RAD23A were identified as key DDR-related genes in MM. Additionally, we explored the drug sensitivity and potential molecular mechanisms associated with each key gene. Altogether, the DDR-related prognostic risk model in MM may facilitate risk stratification and guide treatment decisions, with key prognostic genes might potentially serving as biomarkers and therapeutic targets.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103857"},"PeriodicalIF":3.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144307976","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 : 2025-06-12DOI: 10.1016/j.dnarep.2025.103855
Sri Meghana Yerrapragada , Aleena Alex , Sheera Adar , Michael G. Kemp , M. Alexandra Carpenter
Cell-free DNA (cfDNA) found in biofluids is increasingly being used in the diagnosis and treatment of a variety of disease states, including cancer. Though DNA is known to be susceptible to damage by many different chemotherapeutic compounds and genotoxic agents, the fact that cfDNA may be damaged and contain DNA adducts associated with specific exposures has not previously been considered to any significant extent. Here, using differential centrifugation of culture medium from cells treated with the anti-cancer drug cisplatin, we show that DNA containing cisplatin adducts is readily detectable in the extracellular milieu and is enriched in fractions known to contain small extracellular vesicles and cfDNA. However, our data indicates that this damaged cfDNA is non-vesicular in nature and likely represents fragments of chromatin. Dose and time course experiments suggest that the release of cfDNA containing cisplatin-DNA adducts is correlated with the activation of apoptotic signaling. Indeed, the generation of cisplatin-damaged cfDNA is exacerbated by the loss of nucleotide excision repair and is abrogated by caspase inhibition. Finally, we show that native cisplatin-damaged cfDNA, but not purified, protein-free cfDNA, can be taken up by cells by phagocytosis to result in the presence of cisplatin-DNA adduct-containing DNA in non-cisplatin-treated cells. These results indicate that tumors from patients undergoing cisplatin-based chemotherapy may shed damaged cfDNA that could have additional biological effects in bystander cells, which could both impact chemotherapeutic responses and lead to improved treatments and diagnostic tools for monitoring therapeutic efficacy.
{"title":"Treatment of human cells with the anti-cancer drug cisplatin results in the caspase-dependent release of adduct-containing cell-free DNA","authors":"Sri Meghana Yerrapragada , Aleena Alex , Sheera Adar , Michael G. Kemp , M. Alexandra Carpenter","doi":"10.1016/j.dnarep.2025.103855","DOIUrl":"10.1016/j.dnarep.2025.103855","url":null,"abstract":"<div><div>Cell-free DNA (cfDNA) found in biofluids is increasingly being used in the diagnosis and treatment of a variety of disease states, including cancer. Though DNA is known to be susceptible to damage by many different chemotherapeutic compounds and genotoxic agents, the fact that cfDNA may be damaged and contain DNA adducts associated with specific exposures has not previously been considered to any significant extent. Here, using differential centrifugation of culture medium from cells treated with the anti-cancer drug cisplatin, we show that DNA containing cisplatin adducts is readily detectable in the extracellular milieu and is enriched in fractions known to contain small extracellular vesicles and cfDNA. However, our data indicates that this damaged cfDNA is non-vesicular in nature and likely represents fragments of chromatin. Dose and time course experiments suggest that the release of cfDNA containing cisplatin-DNA adducts is correlated with the activation of apoptotic signaling. Indeed, the generation of cisplatin-damaged cfDNA is exacerbated by the loss of nucleotide excision repair and is abrogated by caspase inhibition. Finally, we show that native cisplatin-damaged cfDNA, but not purified, protein-free cfDNA, can be taken up by cells by phagocytosis to result in the presence of cisplatin-DNA adduct-containing DNA in non-cisplatin-treated cells. These results indicate that tumors from patients undergoing cisplatin-based chemotherapy may shed damaged cfDNA that could have additional biological effects in bystander cells, which could both impact chemotherapeutic responses and lead to improved treatments and diagnostic tools for monitoring therapeutic efficacy.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"151 ","pages":"Article 103855"},"PeriodicalIF":3.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263756","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 : 2025-06-11DOI: 10.1016/j.dnarep.2025.103859
Michele Giaquinto, Alessandro Framarini, Andrea Parlante, Stefan Schoeftner
R-loops are atypical three-stranded nucleic acid structures composed of a stretch of DNA:RNA hybrids that displace the unpaired, single DNA strand, resulting in the formation of a characteristic loop structure. When properly regulated, R-loops have been demonstrated to control crucial processes related to RNA metabolism, epigenetic gene regulation, DNA damage repair, homologous recombination, and DNA replication. However, unscheduled R-loops can induce DNA damage, thus compromising genome stability. In line with these central features, cancer cells frequently exhibit deregulated R-loop metabolism. The action of oncogenes or mutant tumor suppressor genes is associated with alterations in R-loop levels, which in turn can disrupt physiological processes or drive cancer genome instability. A panel of antineoplastic drugs that interfere with R-loop prevention, resolution or processing has been shown to exacerbate R-loop-mediated genome instability, modulate immunity pathways and mediate cell death. Mechanisms of resistance to these drugs are expected to include the activation of pathways that counteract R-loop-mediated genome instability. In this review, we will discuss key regulators of R-loops in cancer cells, therapeutic strategies that promote R-loop formation and the relevance of R-loops for cancer therapy resistance.
{"title":"Harnessing R-loop dynamics: Challenging cancer therapy resistance","authors":"Michele Giaquinto, Alessandro Framarini, Andrea Parlante, Stefan Schoeftner","doi":"10.1016/j.dnarep.2025.103859","DOIUrl":"10.1016/j.dnarep.2025.103859","url":null,"abstract":"<div><div>R-loops are atypical three-stranded nucleic acid structures composed of a stretch of DNA:RNA hybrids that displace the unpaired, single DNA strand, resulting in the formation of a characteristic loop structure. When properly regulated, R-loops have been demonstrated to control crucial processes related to RNA metabolism, epigenetic gene regulation, DNA damage repair, homologous recombination, and DNA replication. However, unscheduled R-loops can induce DNA damage, thus compromising genome stability. In line with these central features, cancer cells frequently exhibit deregulated R-loop metabolism. The action of oncogenes or mutant tumor suppressor genes is associated with alterations in R-loop levels, which in turn can disrupt physiological processes or drive cancer genome instability. A panel of antineoplastic drugs that interfere with R-loop prevention, resolution or processing has been shown to exacerbate R-loop-mediated genome instability, modulate immunity pathways and mediate cell death. Mechanisms of resistance to these drugs are expected to include the activation of pathways that counteract R-loop-mediated genome instability. In this review, we will discuss key regulators of R-loops in cancer cells, therapeutic strategies that promote R-loop formation and the relevance of R-loops for cancer therapy resistance.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103859"},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322419","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 : 2025-06-11DOI: 10.1016/j.dnarep.2025.103858
Sijia Wang , Yukang Wu , Wen Zong , Zhao-Qi Wang
Poly(ADP-ribose) polymerase 1 (PARP1), the founding member of the PARP superfamily, is an enzyme with poly-ADP-ribosyltransferase activity that conducts the majority of poly-ADP-ribosylation (PARylation). PARP1 is the most extensively studied member of the PARP family. It plays a role in various biological processes, particularly in DNA damage repair, including base excision repair, single-strand break repair, double-strand break repair, and maintenance of replication fork stability. Besides DNA damage repair, PARP1 is also involved in the inflammatory response, including, but not limited to, the NF-κB, JAK-STAT, inflammasome assembly, and cGAS-STING signaling pathways. As a scaffold and enzyme, PARP1 and its mediated PARylation induce genotoxic and inflammatory responses to various intracellular and extracellular stressors. Thus, PARP1 has been a target as a pharmaceutical intervention for a range of pathological conditions, including cancer and inflammatory diseases. This review article attempts to provide a comprehensive view of PARP1 as a bridging point between genotoxic and inflammatory responses.
{"title":"\"Yin-Yang\" of PARP1 in genotoxic and inflammatory response","authors":"Sijia Wang , Yukang Wu , Wen Zong , Zhao-Qi Wang","doi":"10.1016/j.dnarep.2025.103858","DOIUrl":"10.1016/j.dnarep.2025.103858","url":null,"abstract":"<div><div>Poly(ADP-ribose) polymerase 1 (PARP1), the founding member of the PARP superfamily, is an enzyme with poly-ADP-ribosyltransferase activity that conducts the majority of poly-ADP-ribosylation (PARylation). PARP1 is the most extensively studied member of the PARP family. It plays a role in various biological processes, particularly in DNA damage repair, including base excision repair, single-strand break repair, double-strand break repair, and maintenance of replication fork stability. Besides DNA damage repair, PARP1 is also involved in the inflammatory response, including, but not limited to, the NF-κB, JAK-STAT, inflammasome assembly, and cGAS-STING signaling pathways. As a scaffold and enzyme, PARP1 and its mediated PARylation induce genotoxic and inflammatory responses to various intracellular and extracellular stressors. Thus, PARP1 has been a target as a pharmaceutical intervention for a range of pathological conditions, including cancer and inflammatory diseases. This review article attempts to provide a comprehensive view of PARP1 as a bridging point between genotoxic and inflammatory responses.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103858"},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144307977","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 : 2025-06-06DOI: 10.1016/j.dnarep.2025.103854
Erika Casari, Renata Tisi, Maria Pia Longhese
Genome integrity is continuously monitored by elaborate cellular networks, collectively referred to as the DNA damage response (DDR), which detect DNA lesions and transmit the information to downstream targets, thereby coordinating a broad range of biological processes. A crucial signal in this response is the generation of single-stranded DNA that, once coated by replication protein A (RPA), serves as a platform for recruiting the apical checkpoint kinase Mec1/ATR. Full activation of Mec1/ATR also requires the 9–1–1 complex, which provides a docking site for additional checkpoint mediators, such as Dpb11/TOPBP1 and Rad9/53BP1. These mediators are important for transducing the checkpoint signal from Mec1/ATR to the effector kinase Rad53/CHK2. The checkpoint signal transduction cascade is tightly regulated by phosphorylation events, which can be counteracted by phosphatases to ensure timely checkpoint inactivation once DNA repair is complete. In this review, we examine the mechanistic aspects of Mec1/ATR activation, with a particular focus on the 9–1–1 checkpoint axis in Saccharomyces cerevisiae. We discuss how phosphorylation and dephosphorylation dynamically regulate the checkpoint pathway, allowing cells to efficiently respond to genotoxic stress while ensuring a timely return to normal cell-cycle progression.
{"title":"Checkpoint activation and recovery: regulation of the 9–1–1 axis by the PP2A phosphatase","authors":"Erika Casari, Renata Tisi, Maria Pia Longhese","doi":"10.1016/j.dnarep.2025.103854","DOIUrl":"10.1016/j.dnarep.2025.103854","url":null,"abstract":"<div><div>Genome integrity is continuously monitored by elaborate cellular networks, collectively referred to as the DNA damage response (DDR), which detect DNA lesions and transmit the information to downstream targets, thereby coordinating a broad range of biological processes. A crucial signal in this response is the generation of single-stranded DNA that, once coated by replication protein A (RPA), serves as a platform for recruiting the apical checkpoint kinase Mec1/ATR. Full activation of Mec1/ATR also requires the 9–1–1 complex, which provides a docking site for additional checkpoint mediators, such as Dpb11/TOPBP1 and Rad9/53BP1. These mediators are important for transducing the checkpoint signal from Mec1/ATR to the effector kinase Rad53/CHK2. The checkpoint signal transduction cascade is tightly regulated by phosphorylation events, which can be counteracted by phosphatases to ensure timely checkpoint inactivation once DNA repair is complete. In this review, we examine the mechanistic aspects of Mec1/ATR activation, with a particular focus on the 9–1–1 checkpoint axis in <em>Saccharomyces cerevisiae</em>. We discuss how phosphorylation and dephosphorylation dynamically regulate the checkpoint pathway, allowing cells to efficiently respond to genotoxic stress while ensuring a timely return to normal cell-cycle progression.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"151 ","pages":"Article 103854"},"PeriodicalIF":3.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241103","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 : 2025-06-01DOI: 10.1016/j.dnarep.2025.103852
Giovannia M. Barbosa, Sarah Delaney
Nucleosome occupancy varies across the genome and plays a critical role in modulating DNA accessibility. While the effect of occupancy on gene expression has been studied, its influence on DNA repair, particularly base excision repair (BER), remains unexplored. In this work, we investigate the relationship between nucleosome occupancy and the initiation of BER by reconstituting nucleosome core particles (NCPs) using four DNA sequences known to modulate nucleosome occupancy in vivo. The results demonstrate that histone-DNA interactions differ significantly among these sequences. Moreover, uracil DNA glycosylase (UDG) activity is limited to solution-accessible uracil (U) lesion sites on NCPs containing the high occupancy sequences M4 and SB. In contrast, UDG displays high activity on NCPs containing the low occupancy sequences M2 and M3, even at less solution accessible lesion sites. In fact, for NCPs containing the sequence with the lowest occupancy, M2, UDG exhibits high activity regardless of the U lesion position. However, this high level of activity regardless of lesion position was not observed for thymine DNA glycosylase (TDG) and single-stranded monofunctional uracil DNA glycosylase 1 (SMUG1). Instead, the activity of TDG was dictated by the sequence flanking the U with a preference for 5′-UpG-3′ and 5′-UpA-3′ sequences, consistent with the role of TDG in epigenetic regulation. SMUG1 activity is high at many U sites but is severely hindered in the dyad region. These results highlight the interplay between nucleosome occupancy and BER, offering new insights into the dynamics of chromatin and DNA repair.
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