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

AT-rich interactive domain-containing protein 1B (ARID1B) has been implicated in DNA damage repair, yet its precise molecular mechanisms and contributions to small cell lung cancer (SCLC) pathogenesis remain incompletely defined. In this study, analysis of clinical datasets revealed ARID1B overexpression in SCLC tissues and cell lines compared to normal lung or lung adenocarcinoma counterparts. Functional studies in vitro and in vivo demonstrated that ARID1B depletion significantly impaired SCLC cell proliferation, clonogenicity, and tumor growth while promoting apoptosis. Mechanistically, During DSB response, ARID1B cooperates with the transcription factor c-MYC to co-activate the expression of key DNA damage repair (DDR) genes (e.g., RNF8 and RAD51 ), Concurrently, ARID1B is recruited to DNA double-strand break (DSB) sites, 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 markedly sensitized SCLC cells to DNA-damaging agents, evidenced by enhanced DNA damage persistence, apoptosis, and tumor growth inhibition in vitro and in vivo . This study unveils a dual regulatory role of ARID1B in homologous recombination (HR) repair of DNA double-strand breaks (DSBs) and establishes ARID1B as a key mediator of chemoresistance in SCLC, highlighting its potential as a therapeutic target to overcome treatment resistance.