biostudies-literatureLang FNational Cancer InstituteNCI NIH HHSNational Institutes of Health1083-1096https://www.ebi.ac.uk/biostudies/studies/S-EPMC11145461biostudies-literatureUnknown26(6)<h4>Background</h4>The cell cycle is tightly regulated by checkpoints, which play a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anticancer treatments, allowing for DNA repair prior to cell division. Manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies.<h4>Methods</h4>In this study, we conducted a forward genome-wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress.<h4>Results</h4>Our findings revealed that canonical DNA repair pathways, including the Ataxia-telangiectasia mutated (ATM)/FancNeuro-oncologyAbrogation of the G2/M checkpoint as a chemosensitization approach for alkylating agents.PMC1114546175N91019D00024Elmogazy OZhang MCappell SDSong HYang CLang FSun ZZhang WAladjem MICornwell JAKaur KAregger MWu XfalseAbrogation of the G2/M checkpoint as a chemosensitization approach for alkylating agents.<h4>Background</h4>The cell cycle is tightly regulated by checkpoints, which play a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anticancer treatments, allowing for DNA repair prior to cell division. Manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies.<h4>Methods</h4>In this study, we conducted a forward genome-wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress.<h4>Results</h4>Our findings revealed that canonical DNA repair pathways, including the Ataxia-telangiectasia mutated (ATM)/Fanc2024-01-01T00:00:00Z2024 Jun2025-04-22T16:58:18.041Z2025-04-06T01:55:04.766ZS-EPMC111454613813488910.1093/neuonc/noad252