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journal article·2025-06Open access

Nuclear‐Localized BCKDK Facilitates Homologous Recombination Repair to Support Breast Cancer Progression and Therapy Resistance

Haiying Liu, Jiaqian Feng, Tingting Pan, Pinggen Zhang, Ling Ye, Zetan Jiang, Zilong Zhou, Qiankun Mao, Jian Li, Xinyi Yang, Ping Gao, De Huang, Huafeng Zhang

Advanced Science· Volume 12· Issue 22
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Source abstract

Abstract

Abstract Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this work shows that nuclear‐localized branched‐chain α‐ketoacid dehydrogenase kinase (BCKDK) acts as a modulator of HRR, promoting cell resistance against DNA damage‐inducing therapy in breast cancer. Mechanistically, this work demonstrates that BCKDK is localized in the nucleus and phosphorylates RNF8 at Ser157, preventing the ubiquitin‐mediated degradation of RAD51, thereby facilitating HRR‐mediated DNA repair under replication stress. Notably, aberrant expression of the BCKDK/p‐RNF8/RAD51 axis correlates with breast cancer progression and poor patient survival. Furthermore, this work identifies a small molecule inhibitor of BCKDK, GSK180736A, that disrupts its HRR function and exhibits strong tumor suppression when combined with DNA damage‐inducing drugs. Collectively, this study reveals a new role of BCKDK in regulating HRR, independent of its metabolic function, presenting it as a potential therapeutic target and predictive biomarker in breast cancer.
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Research context

OpenAlex topics: DNA Repair Mechanisms · PARP inhibition in cancer therapy · Cancer-related Molecular Pathways

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of General Surgery The First Affiliated Hospital of USTC Division of Life Science and Medicine University of Science and Technology of China Hefei 230027 China

Key Laboratory of Immune Response and Immunotherapy School of Basic Medical Sciences Division of Life Science and Medicine University of Science and Technology of China Hefei 230027 China

Medical Research Institute Guangdong Provincial People‘s Hospital Guangdong Academy of Medical Sciences Southern Medical University Guangzhou 510080 China

Center for Advanced Interdisciplinary Science and Biomedicine of IHM Division of Life Sciences and Medicine University of Science and Technology of China Hefei 230001 China

Anhui Key Laboratory of Molecular Oncology Hefei 230026 China

Institute of Health and Medicine Hefei Comprehensive National Science Center Hefei 230601 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Fundamental Research Funds for the Central Universities

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