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，可能会导致基因组不稳定，从而在癌症发展中发挥关键作用。同时，染色质重塑复合物通过调节染色质动力学来决定 DSB 修复途径的选择和编排。然而，NHEJ 和染色质重塑在癌症进展中的相互影响仍不清楚。在这项研究中，GLTSCR1 的缺陷通过促进 NHEJ 修复效率，导致结直肠癌 (CRC) 细胞对 DNA 损伤的抵抗力。从机制上讲，GLTSCR1 与 BRD9 相互作用，参与非规范 BAF 复合体 (GBAF) 的组装。然而，GLTSCR1 缺陷会破坏 GBAF 并引发 BRD9 的泛素化降解。此外，GLTSCR1 缺陷会导致 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。而GLTSCR1及其结合伙伴BRD9并不直接参与NHEJ修复机械的组装；相反，它们调节 NHEJ 修复相关基因的 DNA 可及性。总的来说，我们的研究结果证实 GLTSCR1 缺陷是 CRC 发展中 NHEJ 通路的关键调控事件，这可能需要针对 GLTSCR1 野生型和突变型 CRC 采取不同的治疗策略。© 2024。作者，获得 Springer Nature 独家许可有限的。

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.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.