DNA Repair最新文献

{"title":"DNA-PK inhibitor AZD7648 is a more portent radiosensitizer than PARP inhibitor Olaparib in BRCA1/2 deficient tumors","authors":"Taixiang Wang,&nbsp;Alastair H. Kyle,&nbsp;Jennifer H.E. Baker,&nbsp;Nannan A. Liu,&nbsp;Judit P. Banáth,&nbsp;Sevin Teymori,&nbsp;Andrew I. Minchinton","doi":"10.1016/j.dnarep.2024.103689","DOIUrl":"10.1016/j.dnarep.2024.103689","url":null,"abstract":"<div><p>The effectiveness of radiotherapy depends on the sensitivities of ‘normal’ and cancer cells to the administered radiation dose. Increasing the radiosensitivity of cancers by inhibiting DNA damage repair is a goal of much current research, however success depends on avoiding concomitant sensitization of normal tissues inevitably irradiated during therapy. In this study we investigated the mechanisms of radiosensitization for DNA-PK and PARP inhibitors by examining the impacts on proliferating vs quiescent cell populations. Experiments were performed in <em>BRCA1/2</em>^null and wild-type parental cancer models <em>in vitro</em> and <em>in vivo</em>. Overall AZD7648 has greater radiosensitizing activity relative to Olaparib, with BRCA2-deficient models showing the greatest sensitivity. However, DNA-PK inhibitor AZD7648 also produced greater toxicity in all irradiated mice. While both DNA-PK and PARP inhibition sensitizes wild type tumor cells to radiation, in BRCA1/2 deficient cells PARP inhibition by Olaparib had limited radiosensitization capacity. Quiescent cells are more radioresistant than proliferating cells, and these were also effectively sensitized by AZD7648 while Olaparib was unable to increase radiation-induced cell kill, even in <em>BRCA1/2</em>^null cells. These findings underscore the distinct mechanisms of radiosensitization for DNA-PK and PARP inhibitors. While DNA-PK inhibitors are able to target both proliferating and non-proliferating tumor cells for greater overall anti-cancer benefit, their application is limited by exacerbation of normal tissue toxicities. Conversely, PARP inhibitors exhibit selective activity for proliferating cells, providing a mechanism for targeting activity to cancers, but due to poor activity in non-proliferating cells they have an overall reduced impact on tumor growth control. This study highlights the importance of creating a therapeutic ratio with DNA damage repair inhibition radiation sensitizing strategies.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103689"},"PeriodicalIF":3.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946655","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}

{"title":"Pold4 subunit of replicative polymerase δ promotes fork slowing at broken templates","authors":"Kota Kojima ,&nbsp;Hiromori Ohkubo ,&nbsp;Ryotaro Kawasumi ,&nbsp;Kouji Hirota","doi":"10.1016/j.dnarep.2024.103688","DOIUrl":"10.1016/j.dnarep.2024.103688","url":null,"abstract":"<div><p>Single-strand breaks (SSBs) are the most frequent type of lesion, and replication across such lesions leads to double-strand breaks (DSBs). DSBs that arise during replication are repaired by homologous recombination (HR) and are suppressed by fork reversal. Poly[ADP-ribose] polymerase I (PARP1) and the proofreading exonuclease activity of replicative polymerase ε (Polε) are required for fork reversal when leading strand replication encounters SSBs. However, the mechanism underlying fork reversal at the SSB during lagging-strand replication remains elusive. We here demonstrate that the Pold4 subunit of replicative polymerase δ (Polδ) plays a role in promoting fork reversal during lagging strand replication on a broken template. <em>POLD4</em>^<em>-/-</em> cells exhibited heightened sensitivity to camptothecin (CPT) but not to other DNA-damaging agents compared to wild-type cells. This selective CPT sensitivity in <em>POLD4</em>^<em>-/-</em> cells suggests that Pold4 suppresses DSBs during replication, as CPT induces significant SSBs during replication, which subsequently lead to DSBs. To explore the functional interactions among Pold4, Polε exonuclease, and PARP1 in DSB suppression, we generated <em>PARP1</em>^<em>-/-</em>, <em>POLD4</em>^<em>-/-</em>, Polε exonuclease-deficient <em>POLE1</em>^{<em>exo-/-</em>}, <em>PARP1</em>^<em>-/-</em><em>/POLD4</em>^<em>-/-</em>, and <em>POLD4</em>^<em>-/-</em><em>/POLE1</em>^{<em>exo-/-</em>} cells. These epistasis analyses showed that Pold4 is involved in the PARP1-Polε exonuclease-mediated fork reversal following CPT treatment. These results suggest that Pold4 aids in fork reversal when lagging strand replication stalls on a broken template. In conclusion, the Pold4 subunit of Polδ has roles in the PARP1-Polε exonuclease-mediated fork reversal, contributing to the suppression of DSBs.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103688"},"PeriodicalIF":3.8,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140763790","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}

{"title":"NEIL3: A unique DNA glycosylase involved in interstrand DNA crosslink repair","authors":"Leah E. Oswalt ,&nbsp;Brandt F. Eichman","doi":"10.1016/j.dnarep.2024.103680","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103680","url":null,"abstract":"<div><p>Endonuclease VIII-like 3 (NEIL3) is a versatile DNA glycosylase that repairs a diverse array of chemical modifications to DNA. Unlike other glycosylases, NEIL3 has a preference for lesions within single-strand DNA and at single/double-strand DNA junctions. Beyond its canonical role in base excision repair of oxidized DNA, NEIL3 initiates replication-dependent interstrand DNA crosslink repair as an alternative to the Fanconi Anemia pathway. This review outlines our current understanding of NEIL3’s biological functions, role in disease, and three-dimensional structure as it pertains to substrate specificity and catalytic mechanism.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103680"},"PeriodicalIF":3.8,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000569/pdfft?md5=f79831f8a25151a8efdb4bb77e08b28f&pid=1-s2.0-S1568786424000569-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140646716","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}

{"title":"DNA repair deficiencies and neurodegeneration","authors":"Baptiste Ropert ,&nbsp;Christian Gallrein ,&nbsp;Björn Schumacher","doi":"10.1016/j.dnarep.2024.103679","DOIUrl":"10.1016/j.dnarep.2024.103679","url":null,"abstract":"<div><p>Neurodegenerative diseases are the second most prevalent cause of death in industrialized countries. Alzheimer’s Disease is the most widespread and also most acknowledged form of dementia today. Together with Parkinson’s Disease they account for over 90 % cases of neurodegenerative disorders caused by proteopathies. Far less known are the neurodegenerative pathologies in DNA repair deficiency syndromes. Such diseases like Cockayne - or Werner Syndrome are described as progeroid syndromes – diseases that cause the premature ageing of the affected persons, and there are clear implications of such diseases in neurologic dysfunction and degeneration. In this review, we aim to draw the attention on commonalities between proteopathy-associated neurodegeneration and neurodegeneration caused by DNA repair defects and discuss how mitochondria are implicated in the development of both disorder classes. Furthermore, we highlight how nematodes are a valuable and indispensable model organism to study conserved neurodegenerative processes in a fast-forward manner.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"138 ","pages":"Article 103679"},"PeriodicalIF":3.8,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000557/pdfft?md5=3327f387b995932786f0abdcf14eb3ac&pid=1-s2.0-S1568786424000557-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140610184","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}

{"title":"Genomic stress and impaired DNA repair in Alzheimer disease","authors":"Jolien Neven ,&nbsp;Luidy Kazuo Issayama,&nbsp;Ilse Dewachter,&nbsp;David M. Wilson III","doi":"10.1016/j.dnarep.2024.103678","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103678","url":null,"abstract":"<div><p>Alzheimer disease (AD) is the most prominent form of dementia and has received considerable attention due to its growing burden on economic, healthcare and basic societal infrastructures. The two major neuropathological hallmarks of AD, i.e., extracellular amyloid beta (Aβ) peptide plaques and intracellular hyperphosphorylated Tau neurofibrillary tangles, have been the focus of much research, with an eye on understanding underlying disease mechanisms and identifying novel therapeutic avenues. One often overlooked aspect of AD is how Aβ and Tau may, through indirect and direct mechanisms, affect genome integrity. Herein, we review evidence that Aβ and Tau abnormalities induce excessive genomic stress and impair genome maintenance mechanisms, events that can promote DNA damage-induced neuronal cell loss and associated brain atrophy.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103678"},"PeriodicalIF":3.8,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140647235","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}

{"title":"CometChip enables parallel analysis of multiple DNA repair activities [DNA repair 106 (2021) 103176–103202]","authors":"Jing Ge ,&nbsp;Le P. Ngo ,&nbsp;Simran Kaushal ,&nbsp;Ian J. Tay ,&nbsp;Elina Thadhani ,&nbsp;Jennifer E. Kay ,&nbsp;Patrizia Mazzucato ,&nbsp;Danielle Chow ,&nbsp;Jessica Fessler ,&nbsp;David M. Weingeist ,&nbsp;Robert W. Sobol ,&nbsp;Leona D. Samson ,&nbsp;Scott R. Floyd ,&nbsp;Bevin P. Engelward","doi":"10.1016/j.dnarep.2024.103677","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103677","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"138 ","pages":"Article 103677"},"PeriodicalIF":3.8,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000533/pdfft?md5=e2c7d94a15fc06bbaf21f2ae108998fa&pid=1-s2.0-S1568786424000533-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140350226","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}

{"title":"SMC-5/6 complex subunit NSE-1 plays a crucial role in meiosis and DNA repair in Caenorhabditis elegans","authors":"Arome Solomon Odiba ,&nbsp;Chiemekam Samuel Ezechukwu ,&nbsp;Guiyan Liao ,&nbsp;Ye Hong ,&nbsp;Wenxia Fang ,&nbsp;Cheng Jin ,&nbsp;Anton Gartner ,&nbsp;Bin Wang","doi":"10.1016/j.dnarep.2024.103669","DOIUrl":"10.1016/j.dnarep.2024.103669","url":null,"abstract":"<div><p>The SMC5/6 complex is evolutionarily conserved across all eukaryotes and plays a pivotal role in preserving genomic stability. Mutations in genes encoding SMC5/6 complex subunits have been associated with human lung disease, immunodeficiency, and chromosome breakage syndrome. Despite its critical importance, much about the SMC5/6 complex remains to be elucidated. Various evidences have suggested possible role of a subunit of the SMC5/6 complex, NSE1, in chromosome segregation and DNA repair. Current knowledge regarding the role of NSE1 is primarily derived from single-cell-based analyses in yeasts, <em>Arabidopsis thaliana</em>, and human cell lines. However, our understanding of its function is still limited and requires further investigation. This study delves into the role of <em>nse-1</em> in <em>Caenorhabditis elegans</em>, revealing its involvement in meiotic recombination and DNA repair. <em>nse-1</em> mutants display reduced fertility, increased male incidence, and increased sensitivity to genotoxic chemicals due to defects in meiotic chromosome segregation and DNA repair. These defects manifest as increased accumulation of RAD-51 foci, increased chromosome fragmentation, and susceptibility to MMS, cisplatin, and HU. Furthermore, <em>nse-1</em> mutation exacerbates germ cell death by upregulating <em>ced-13</em> and <em>egl-1</em> genes involved in the CEP-1/p53-mediated apoptotic pathway. NSE-1 is essential for the proper localization of NSE-4 and MAGE-1 on the chromosomes. Collectively, these findings firmly establish <em>nse-1</em> as a crucial factor in maintaining genomic stability.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"137 ","pages":"Article 103669"},"PeriodicalIF":3.8,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140148325","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}

{"title":"Mitochondrial transcription factor A (TFAM) has 5′-deoxyribose phosphate lyase activity in vitro","authors":"Wenxin Zhao ,&nbsp;Adil S. Hussen ,&nbsp;Bret D. Freudenthal ,&nbsp;Zucai Suo ,&nbsp;Linlin Zhao","doi":"10.1016/j.dnarep.2024.103666","DOIUrl":"10.1016/j.dnarep.2024.103666","url":null,"abstract":"<div><p>Mitochondrial DNA (mtDNA) plays a key role in mitochondrial and cellular functions. mtDNA is maintained by active DNA turnover and base excision repair (BER). In BER, one of the toxic repair intermediates is 5′-deoxyribose phosphate (5′dRp). Human mitochondrial DNA polymerase γ has weak dRp lyase activities, and another known dRp lyase in the nucleus, human DNA polymerase β, can also localize to mitochondria in certain cell and tissue types. Nonetheless, whether additional proteins have the ability to remove 5'dRp in mitochondria remains unknown. Our prior work on the AP lyase activity of mitochondrial transcription factor A (TFAM) has prompted us to examine its ability to remove 5′dRp residues in vitro. TFAM is the primary DNA-packaging factor in human mitochondria and interacts with mitochondrial DNA extensively. Our data demonstrate that TFAM has the dRp lyase activity with different DNA substrates. Under single-turnover conditions, TFAM removes 5′dRp residues at a rate comparable to that of DNA polymerase (pol) β, albeit slower than that of pol λ. Among the three proteins examined, pol λ shows the highest single-turnover rates in dRp lyase reactions. The catalytic effect of TFAM is facilitated by lysine residues of TFAM via Schiff base chemistry, as evidenced by the observation of dRp-lysine adducts in mass spectrometry experiments. The catalytic effect of TFAM observed here is analogous to the AP lyase activity of TFAM reported previously. Together, these results suggest a potential role of TFAM in preventing the accumulation of toxic DNA repair intermediates.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"137 ","pages":"Article 103666"},"PeriodicalIF":3.8,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097878","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}

{"title":"Comparing Mfd- and UvrD-dependent models of transcription coupled DNA repair in live Escherichia coli using single-molecule tracking","authors":"Elżbieta Kaja ,&nbsp;Donata Vijande ,&nbsp;Justyna Kowalczyk ,&nbsp;Michał Michalak ,&nbsp;Jacek Gapiński ,&nbsp;Carolin Kobras ,&nbsp;Philippa Rolfe ,&nbsp;Mathew Stracy","doi":"10.1016/j.dnarep.2024.103665","DOIUrl":"10.1016/j.dnarep.2024.103665","url":null,"abstract":"<div><p>During transcription-coupled DNA repair (TCR) the detection of DNA damage and initiation of nucleotide excision repair (NER) is performed by translocating RNA polymerases (RNAP), which are arrested upon encountering bulky DNA lesions. Two opposing models of the subsequent steps of TCR in bacteria exist. In the first model, stalled RNAPs are removed from the damage site by recruitment of Mfd which dislodges RNAP by pushing it forwards before recruitment of UvrA and UvrB. In the second model, UvrD helicase backtracks RNAP from the lesion site. Recent studies have proposed that both UvrD and UvrA continuously associate with RNAP before damage occurs, which forms the primary damage sensor for NER. To test these two models of TCR in living <em>E. coli</em>, we applied super-resolution microscopy (PALM) combined with single particle tracking to directly measure the mobility and recruitment of Mfd, UvrD, UvrA, and UvrB to DNA during ultraviolet-induced DNA damage. The intracellular mobilities of NER proteins in the absence of DNA damage showed that most UvrA molecules could in principle be complexed with RNAP, however, this was not the case for UvrD. Upon DNA damage, Mfd recruitment to DNA was independent of the presence of UvrA, in agreement with its role upstream of this protein in the TCR pathway. In contrast, UvrD recruitment to DNA was strongly dependent on the presence of UvrA. Inhibiting transcription with rifampicin abolished Mfd DNA-recruitment following DNA damage, whereas significant UvrD, UvrA, and UvrB recruitment remained, consistent with a UvrD and UvrA performing their NER functions independently of transcribing RNAP. Together, although we find that up to ∼8 UvrD-RNAP-UvrA complexes per cell could potentially form in the absence of DNA damage, our live-cell data is not consistent with this complex being the primary DNA damage sensor for NER.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"137 ","pages":"Article 103665"},"PeriodicalIF":3.8,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097629","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}

{"title":"What are the DNA lesions underlying formaldehyde toxicity?","authors":"Bente Benedict,&nbsp;Stella Munkholm Kristensen,&nbsp;Julien P. Duxin","doi":"10.1016/j.dnarep.2024.103667","DOIUrl":"10.1016/j.dnarep.2024.103667","url":null,"abstract":"<div><p>Formaldehyde is a highly reactive organic compound. Humans can be exposed to exogenous sources of formaldehyde, but formaldehyde is also produced endogenously as a byproduct of cellular metabolism. Because formaldehyde can react with DNA, it is considered a major endogenous source of DNA damage. However, the nature of the lesions underlying formaldehyde toxicity in cells remains vastly unknown. Here, we review the current knowledge of the different types of nucleic acid lesions that are induced by formaldehyde and describe the repair pathways known to counteract formaldehyde toxicity. Taking this knowledge together, we discuss and speculate on the predominant lesions generated by formaldehyde, which underly its natural toxicity.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"138 ","pages":"Article 103667"},"PeriodicalIF":3.8,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097879","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}