biostudies-literatureZhou JNational Key R&D Program of ChinaScience and Technology Planning Project of Guangdong ProvinceGuangdong Esophageal Cancer Institute Science and Technology Program2023 Guangzhou Basic and Applied Basic Research ProjectNational Natural Science Foundation of ChinaNational Key Research and Development Program of Chinae2302494https://www.ebi.ac.uk/biostudies/studies/S-EPMC10754142biostudies-literatureUnknown10(36)Stromal antigen 2 (STAG2), a subunit of the cohesin complex, is recurrently mutated in various tumors. However, the role of STAG2 in DNA repair and its therapeutic implications are largely unknown. Here it is reported that knockout of STAG2 results in increased double-stranded breaks (DSBs) and chromosomal aberrations by reducing homologous recombination (HR) repair, and confers hypersensitivity to inhibitors of ataxia telangiectasia mutated (ATMi), Poly ADP Ribose Polymerase (PARPi), or the combination of both. Of note, the impaired HR by STAG2-deficiency is mainly attributed to the restored expression of KMT5A, which in turn methylates H4K20 (H4K20me0) to H4K20me1 and thereby decreases the recruitment of BRCA1-BARD1 to chromatin. Importantly, STAG2 expression correlates with poor prognosAdvanced science (Weinheim, Baden-Wurttemberg, Germany)STAG2 Regulates Homologous Recombination Repair and Sensitivity to ATM Inhibition.PMC107541428207318982172646822029052021YFA13002018187200181972227M202108823731902020B1212060023SL2022A04J01968Lin PLin WPChen JWZhu TCZhang YCXie JJD'Andrea ADCai XXXie DNie RCYin YXXiang ZCCai MYWang XHe ZPZhou JfalseSTAG2 Regulates Homologous Recombination Repair and Sensitivity to ATM Inhibition.Stromal antigen 2 (STAG2), a subunit of the cohesin complex, is recurrently mutated in various tumors. However, the role of STAG2 in DNA repair and its therapeutic implications are largely unknown. Here it is reported that knockout of STAG2 results in increased double-stranded breaks (DSBs) and chromosomal aberrations by reducing homologous recombination (HR) repair, and confers hypersensitivity to inhibitors of ataxia telangiectasia mutated (ATMi), Poly ADP Ribose Polymerase (PARPi), or the combination of both. Of note, the impaired HR by STAG2-deficiency is mainly attributed to the restored expression of KMT5A, which in turn methylates H4K20 (H4K20me0) to H4K20me1 and thereby decreases the recruitment of BRCA1-BARD1 to chromatin. Importantly, STAG2 expression correlates with poor prognos2023-01-01T00:00:00Z2023 Dec2026-07-15T00:33:25.362Z2025-04-06T19:18:32.072ZS-EPMC107541423798583910.1002/advs.202302494