BTAF1: a key regulator of DNA end resection and predictor of chemotherapy sensitivity in gastric cancer.

BTAF1, an ATP-dependent remodeler of the TBP-DNA complex, is frequently mutated in gastric cancer. However, its role in DNA repair and therapeutic relevance remains largely undefined. Here, we show that BTAF1 knockout leads to accumulation of double-strand breaks (DSBs) by impairing DNA end-resection process of homologous recombination (HR) repair, thereby sensitizing cells to genotoxic agents both in vitro and in vivo. Mechanistically, BTAF1 prevents ubiquitin-mediated degradation of MRE11, maintaining its protein stability, promoting DNA end resection and HR, and consequently enhancing cellular resistance to DNA-damaging stress. Notably, the interaction between BTAF1 and MRE11 is dynamically regulated by PARP1-mediated PARylation of BTAF1 during the DNA damage response. Loss of BTAF1 also increases chemosensitivity in gastric cancer xenograft and organoid models. Clinically, high BTAF1 expression correlates with poor prognosis in gastric cancer patients receiving neoadjuvant chemotherapy. Collectively, our findings identify BTAF1 as a critical regulator of HR repair through stabilization of MRE11 and propose BTAF1 as a potential biomarker for predicting response to genotoxic chemotherapy. BTAF1 is frequently mutated in gastric cancer, yet its role in DNA repair remains unclear. BTAF1 promotes homologous recombination and chemoresistance in gastric cancer by stabilizing MRE11. BTAF1 loss impairs DNA end resection, sensitizing cells to genotoxic agents. The BTAF1-MRE11 interaction is regulated by PARP1 mediated PARylation.