ARID1B promotes DNA end resection via MDC1 and co-transactivation of DNA repair genes with c-MYC in small cell lung cancer

Abstract

Abstract AT-rich interactive domain-containing protein 1B (ARID1B) has been implicated in DNA damage repair; however, its precise molecular mechanisms and contributions to small cell lung cancer (SCLC) pathogenesis remain incompletely defined. In this study, analysis of clinical datasets revealed that ARID1B is significantly overexpressed in SCLC tissues and cell lines compared to normal lung tissues or lung adenocarcinoma counterparts. Functional studies in vitro and in vivo demonstrated that ARID1B depletion markedly impairs SCLC cell proliferation, clonogenicity, and tumor growth while accelerating apoptosis. Mechanistically, during the DNA double-strand break (DSB) response, ARID1B cooperates with the transcription factor c-MYC to co-activate the transcription of key DNA damage repair (DDR) genes, such as RNF8 and RAD51 . Concurrently, ARID1B is rapidly recruited to DSB sites, where it facilitates single-stranded DNA (ssDNA) formation via end resection and promotes the recruitment of MDC1, a scaffold protein essential for early DDR signaling. Critically, ARID1B deficiency profoundly sensitizes SCLC cells to DNA-damaging agents, as evidenced by enhanced DNA damage persistence, apoptosis, and tumor growth inhibition in vitro and in vivo. Taken together, this study unveils a dual regulatory role of ARID1B in homologous recombination (HR) repair and establishes its potential as a therapeutic target to potentiate the efficacy of frontline chemotherapy in SCLC.