Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China.
School of Basic Medical Science, The Fourth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
Oncogene. 2024 Nov;43(48):3517-3531. doi: 10.1038/s41388-024-03179-x. Epub 2024 Oct 11.
Non-homologous end joining (NHEJ), as one major pathway of DNA double-strand break (DSB) repair, could cause genomic instability, which plays pivotal roles in cancer development. While, chromatin remodeling complexes dictate the selection and orchestration of DSB repair pathways by regulating chromatin dynamics. However, the crosstalk between NHEJ and chromatin remodeling in cancer progress remains unclear. In this study, deficiency of GLTSCR1 causes resistance to DNA damage in colorectal cancer (CRC) cells by promoting NHEJ repair efficiency. Mechanistically, GLTSCR1 interacts with BRD9 to engage in the assembly of the non-canonical BAF complex (GBAF). However, GLTSCR1 deficiency disrupts GBAF and triggers the ubiquitination degradation of BRD9. Furthermore, GLTSCR1 deficiency causes aberrant opening in the promoter region of NHEJ repair-associated genes, which promotes CRC development. While, GLTSCR1 and its binding partner BRD9 are not directly involved in assembling NHEJ repair machinery; instead, they regulate the DNA accessibility of NHEJ repair-associated genes. Collectively, our findings confirm GLTSCR1 deficiency as a critical regulatory event of the NHEJ pathway in CRC development, which might require different therapeutic strategy for GLTSCR1 wild-type and mutant CRC.
非同源末端连接（NHEJ）作为 DNA 双链断裂（DSB）修复的主要途径之一，可导致基因组不稳定，在癌症发展中起着关键作用。而染色质重塑复合物通过调节染色质动力学来决定 DSB 修复途径的选择和协调。然而，NHEJ 和染色质重塑在癌症进展中的相互作用尚不清楚。在这项研究中，GLTSCR1 的缺失通过促进 NHEJ 修复效率导致结直肠癌细胞（CRC）对 DNA 损伤产生抗性。在机制上，GLTSCR1 与 BRD9 相互作用，参与形成非典型 BAF 复合物（GBAF）。然而，GLTSCR1 的缺失会破坏 GBAF 并触发 BRD9 的泛素化降解。此外，GLTSCR1 的缺失导致与 NHEJ 修复相关基因的启动子区域异常开放，从而促进 CRC 的发展。然而，GLTSCR1 和其结合伴侣 BRD9 并不直接参与组装 NHEJ 修复机制；相反，它们调节与 NHEJ 修复相关基因的 DNA 可及性。总之，我们的研究结果证实 GLTSCR1 的缺失是 CRC 发展中 NHEJ 途径的关键调节事件，这可能需要针对 GLTSCR1 野生型和突变型 CRC 采用不同的治疗策略。
