GLTSCR1 deficiency promotes colorectal cancer development through regulating non-homologous end joining.

Abstract

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.