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

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Title: BTAF1: a key regulator of DNA end resection and predictor of chemotherapy sensitivity in gastric cancer.
Authors: Xie JJ; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.; Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China., Lin JL; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China., Xiang ZC; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China., Qu CH; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China., Cai XX; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China., Nie RC; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.; Department of Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China., Lin P; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.; Department of Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China., Yin YX; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China., Duan JL; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China. duanjl@sysucc.org.cn.; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China. duanjl@sysucc.org.cn., Xie D; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China. xiedan@sysucc.org.cn.; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China. xiedan@sysucc.org.cn., Cai MY; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China. caimy@sysucc.org.cn.; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China. caimy@sysucc.org.cn.
Source: Cell death and differentiation [Cell Death Differ] 2026 Oct; Vol. 33 (10), pp. 1994-2006. Date of Electronic Publication: 2026 Mar 17.
Publication Type: Journal Article; Research Support, Non-U.S. Gov't
Language: English
Journal Info: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9437445 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5403 (Electronic) Linking ISSN: 13509047 NLM ISO Abbreviation: Cell Death Differ Subsets: MEDLINE
Imprint Name(s): Publication: <2003->: London : Nature Publishing Group
Original Publication: London : Edward Arnold, c1994-
MeSH Terms: Stomach Neoplasms*/drug therapy , Stomach Neoplasms*/genetics , Stomach Neoplasms*/pathology , Stomach Neoplasms*/metabolism, MRE11 Homologue Protein/metabolism ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Humans ; Animals ; Cell Line, Tumor ; DNA Breaks, Double-Stranded ; Mice ; Drug Resistance, Neoplasm
Abstract: 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.
(© 2026. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: Institutional Review Board approval (Sun Yat-sen University Cancer Center) the protocol (B2023-335-01) and informed consent were obtained prior to tissue acquisition and analysis. Animal ethics are listed in the Materials and Methods section.
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Grant Information: 82172646 National Natural Science Foundation of China (National Science Foundation of China); 82373190 National Natural Science Foundation of China (National Science Foundation of China)
Substance Nomenclature: EC 3.1.- (MRE11 Homologue Protein)
0 (MRE11 protein, human)
EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
Entry Date(s): Date Created: 20260318 Date Completed: 20261001 Latest Revision: 20261005
Update Code: 20261005
PubMed Central ID: PMC13631330
DOI: 10.1038/s41418-026-01709-6
PMID: 41844894
Database: MEDLINE
Description
ISSN:1476-5403
DOI:10.1038/s41418-026-01709-6