2. Academic Validation
  3. BMAL1 collaborates with CLOCK to directly promote DNA double-strand break repair and tumor chemoresistance

BMAL1 collaborates with CLOCK to directly promote DNA double-strand break repair and tumor chemoresistance

  • Oncogene. 2023 Feb 2. doi: 10.1038/s41388-023-02603-y.
Canfeng Zhang # 1,  Liping Chen # 2,  Lu Sun # 3,  Heping Jin 4 5,  Kai Ren 3,  Shiqi Liu 4 5,  Yongyu Qian 4 5,  Shupeng Li 6,  Fangping Li 3,  Chengming Zhu 3,  Yong Zhao 4 5,  Haiying Liu 4 5,  Yan Liu 7
Affiliations

Affiliations

  • 1 The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China. zhangcf6@mail2.sysu.edu.cn.
  • 2 The Center for Medical Research, The First People's Hospital of Nanning City, Nanning, 530021, China.
  • 3 The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China.
  • 4 MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510006, China.
  • 6 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • 7 The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China. liuyan92@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 36725890 DOI: 10.1038/s41388-023-02603-y
Abstract

Accumulating evidence indicates a correlation between circadian dysfunction and genomic instability. However, whether the circadian machinery directly regulates DNA damage repair, especially in double-strand breaks (DSBs), remains poorly understood. Here, we report that in response to DSBs, BMAL1 is activated by ATM-mediated phosphorylation at S183. Phosphorylated BMAL1 is then localized to DNA damage sites, where it facilitates acetylase CLOCK to load in the chromatin, regulating the acetylation of histone H4 (H4Ac) at DSB sites. In this way, the BMAL1-CLOCK-H4Ac axis promotes the DNA end-resection to generate single-stranded DNA (ssDNA) and the subsequent homologous recombination (HR). BMAL1 deficient cells display defective HR, accumulation of unrepaired DSBs and genome instability. Accordingly, depletion of BMAL1 significantly enhances the sensitivity of adrenocortical carcinoma (ACC) to DNA damage-based therapy in vitro and in vivo. These findings uncover non-canonical function of BMAL1 and CLOCK in HR-mediated DSB repair, which may have an implication in Cancer therapeutics.

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