State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Guangxi International Travel Healthcare Centre (Port Clinic of Nanning Customs District), Nanning, Guangxi, 530021, China.
Adv Sci (Weinh). 2023 Dec;10(36):e2302494. doi: 10.1002/advs.202302494. Epub 2023 Nov 20.
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 prognosis of cancer patients. STAG2 is identified as an important regulator of HR and a potential therapeutic strategy for STAG2-mutant tumors is elucidated.
基质抗原 2（STAG2）是黏合复合物的亚基，在各种肿瘤中经常发生突变。然而，STAG2 在 DNA 修复中的作用及其治疗意义在很大程度上尚不清楚。本研究报道称，敲除 STAG2 可通过减少同源重组（HR）修复导致双链断裂（DSBs）和染色体畸变，并增加对共济失调毛细血管扩张突变（ATM）抑制剂、聚 ADP 核糖聚合酶（PARPi）或两者联合的敏感性。值得注意的是，STAG2 缺失导致的 HR 受损主要归因于 KMT5A 的恢复表达，KMT5A 可将 H4K20（H4K20me0）甲基化为 H4K20me1，从而减少 BRCA1-BARD1 向染色质的募集。重要的是，STAG2 的表达与癌症患者的预后不良相关。本研究确定了 STAG2 是 HR 的重要调节因子，并阐明了针对 STAG2 突变肿瘤的潜在治疗策略。
