{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T21:30:22Z","timestamp":1767043822043,"version":"3.48.0"},"reference-count":103,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Genetics"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The DNA Damage Repair (DDR) signaling pathway serves as a crucial molecular hub that regulates chemotherapy efficacy, offering significant translational value in the field of precision oncology. This review systematically analyzes the molecular mechanisms of five core DDR pathways (Homologous Recombination Repair, Non\u2010Homologous End Joining, Base Excision Repair, Nucleotide Excision Repair, and Mismatch Repair) in mediating chemotherapy resistance in tumors, and thoroughly elucidates the correlation between key molecular events\u2014such as BRCA1\/2 deficiency, MMR functional abnormalities, and Ataxia Telangiectasia Mutated\/Ataxia Telangiectasia and Rad3\u2010related (ATM\/ATR) signaling pathway dysregulation\u2014and chemotherapy sensitivity. The DDR deficiency biomarker system established through the integration of multi\u2010omics data provides molecular classification tools for predicting the efficacy of platinum\u2010based drugs. This study focuses on the mechanism by which Poly ADP\u2010Ribose Polymerase inhibitors reverse Homologous Recombination\u2010Deficient tumor resistance through \u201csynthetic lethality\u201d effects while also revealing the synergistic anti\u2010tumor effects of ATM\/ATR inhibitors in combination with chemotherapeutic agents. The research presents an innovative molecular synergy model between DDR regulation and Immune Checkpoint Blockade, confirming that tumor neoantigen release induced by DDR deficiency can enhance immunotherapy responses. This article also provides perspectives on multidimensional intervention strategies based on the DDR network, including the development of inhibitors targeting novel DDR targets, the establishment of DDR pathway functional assessment systems based on multidimensional biomarkers, and the investigation of synergistic paradigms between DDR and novel therapeutic modalities. Additionally, we explore the dynamic evolution mechanisms of DDR\u2010mediated chemotherapy resistance by analyzing the interactions between DDR and metabolic reprogramming, as well as other related processes. These breakthrough advances provide theoretical foundations and innovative directions for overcoming chemotherapy resistance and advancing personalized treatment, marking a new era in cancer therapy characterized by precision targeting of DDR pathways.<\/jats:p>","DOI":"10.1002\/ggn2.202500036","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T14:51:13Z","timestamp":1766415073000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Translational Aspects of DNA Damage Repair in Optimizing Cancer Chemotherapy"],"prefix":"10.1002","volume":"6","author":[{"given":"Anqi","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Oncology Zhujiang Hospital Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinyue","family":"He","sequence":"additional","affiliation":[{"name":"Department of Oncology Zhujiang Hospital Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aimin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Urology Changhai Hospital Naval Medical University (Second Military Medical University)  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology Zhujiang Hospital Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University  Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hengguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"College &amp; Hospital of Stomatology Key Lab. of Oral Diseases Research of Anhui Province Anhui Medical University Hefei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjun","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Wuxi People's Hospital Wuxi Medical Center The Affiliated Wuxi People's Hospital of Nanjing Medical University Nanjing Medical University  Wuxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8215-2045","authenticated-orcid":false,"given":"Peng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Oncology Zhujiang Hospital Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E22\u201011\u20100518"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010022\u201002469\u20100"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr\u201023\u2010742"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202304702"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.488"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.943090"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935\u2010020\u201001639\u20104"},{"issue":"1","key":"e_1_2_12_9_1","article-title":"Peptides for Dual Targeting of ErbB1 and ErbB2: Blocking EGFR Cell Signaling Transduction Pathways for Cancer Chemotherapy","volume":"17","author":"Patnaik S. K.","year":"2024","journal-title":"Curr Mol Pharmacol"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.770811"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/8766448"},{"issue":"4","key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.molcel.2015.10.040","article-title":"Targeting the DNA Damage Response in Cancer","volume":"60","author":"O'Connor M. J.","year":"2015","journal-title":"Molecular Cell"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17122087"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes14071346"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/10732748241261539"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semradonc.2021.09.004"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1515\/med\u20102024\u20100981"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023022884"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2024.189171"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010023\u201006084\u20105"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.7224"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm\u201020\u20102920"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.23761"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000526415"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010024\u201003078\u20109"},{"issue":"1","key":"e_1_2_12_26_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41573-022-00558-5","article-title":"Targeting Replication Stress in Cancer Therapy","volume":"22","author":"Costa A. A. B. A.","year":"2023","journal-title":"Nat Rev Drug Discovery"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.388"},{"issue":"8","key":"e_1_2_12_28_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2024.103630","article-title":"Understanding Homologous Recombination Repair Deficiency in Biliary Tract Cancers: Clinical Implications and Correlation with Platinum Sensitivity","volume":"9","author":"Mavroeidi I. A.","year":"2024","journal-title":"ESMO Open"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867325666180214113154"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054741"},{"issue":"5","key":"e_1_2_12_31_1","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1042\/EBC20200013","article-title":"Base Excision Repair and Its Implications to Cancer Therapy","volume":"64","author":"Grundy G. J.","year":"2020","journal-title":"Essays in Biochemistry"},{"issue":"7","key":"e_1_2_12_32_1","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.1093\/nar\/gkaa151","article-title":"The Ligation of Pol \u03b2 Mismatch Insertion Products Governs the Formation of Promutagenic Base Excision DNA Repair Intermediates","volume":"48","author":"\u00c7a\u011flayan M.","year":"2020","journal-title":"Nucleic Acids Research"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00595\u2010015\u20101270\u20108"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1631\/jzus.B2000344"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CB00101A"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2015.09.003"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1209507110"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.35267"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2023.117338"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15143642"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202403485"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M603667200"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.875132"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.05.015"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.08.2509"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature24060"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201019\u20103529"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.31083\/j.fbl2810234"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1423684"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277\u2010024\u201005785\u2010x"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201006688\u20105"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a000893"},{"issue":"1","key":"e_1_2_12_53_1","article-title":"Targeting Mutant\u2010p53 for Cancer Treatment: Are We There Yet?","volume":"17","author":"Lim D. V.","year":"2024","journal-title":"Curr Mol Pharmacol"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.130351"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1011"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010pathol\u2010012615\u2010044438"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12015\u2010023\u201010639\u20106"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.116043"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.027"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201006817\u20100"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpan.2024.12.002"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S205633"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpan.2024.11.001"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.334516.119"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg761"},{"key":"e_1_2_12_66_1","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2020.564601","article-title":"PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance","volume":"8","author":"Rose M.","year":"2020","journal-title":"Frontiers in Cell and Developmental Biology"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1436563"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax6367"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.22058"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12244"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.08.025"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201013\u20100110"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2025.2489720"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.123.001971"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16061139"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2010.06.006"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25147725"},{"key":"e_1_2_12_78_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.MCT\u201019\u20100946"},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.1007\/s42764\u2010021\u201000047\u2010w"},{"key":"e_1_2_12_80_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.MCT\u201023\u20100681"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S208720"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23084264"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2024.03.057"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201011\u20100320"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201010\u20100984"},{"key":"e_1_2_12_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188521"},{"key":"e_1_2_12_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2023.188910"},{"key":"e_1_2_12_88_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010023\u201001934\u20100"},{"key":"e_1_2_12_89_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000867"},{"key":"e_1_2_12_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpan.2024.12.001"},{"key":"e_1_2_12_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010019\u20100046\u2010z"},{"key":"e_1_2_12_92_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1016574108"},{"key":"e_1_2_12_93_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/978-3-031-30065-3_9","article-title":"Combining Poly (ADP\u2010Ribose) Polymerase (PARP) Inhibitors with Chemotherapeutic Agents: Promise and Challenges","volume":"186","author":"Thein K. Z.","year":"2023","journal-title":"Cancer Treatment and Research"},{"key":"e_1_2_12_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2021.03.001"},{"key":"e_1_2_12_95_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2024.117970"},{"key":"e_1_2_12_96_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00015"},{"key":"e_1_2_12_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrrev.2013.07.001"},{"key":"e_1_2_12_98_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2024.149907"},{"key":"e_1_2_12_99_1","doi-asserted-by":"publisher","DOI":"10.1002\/imt2.130"},{"key":"e_1_2_12_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2021.103245"},{"key":"e_1_2_12_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.09.016"},{"issue":"7","key":"e_1_2_12_102_1","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1158\/2159-8290.CD-17-0226","article-title":"DNA Damage and Repair Biomarkers of Immunotherapy Response","volume":"7","author":"Mouw K. W.","year":"2017","journal-title":"Cancer Discovery"},{"key":"e_1_2_12_103_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.708294"},{"key":"e_1_2_12_104_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI123319"}],"container-title":["Advanced Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ggn2.202500036","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T21:25:38Z","timestamp":1767043538000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/ggn2.202500036"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":103,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/ggn2.202500036"],"URL":"https:\/\/doi.org\/10.1002\/ggn2.202500036","archive":["Portico"],"relation":{},"ISSN":["2641-6573","2641-6573"],"issn-type":[{"type":"print","value":"2641-6573"},{"type":"electronic","value":"2641-6573"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-06-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00036"}}