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The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair

Lingyu Qiu1, Wenchao Xu1, Xiaopeng Lu1

  • 1International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China.

Nucleic Acids Research
|July 28, 2023
PubMed

Insights

Histone deacetylase 6 (HDAC6) negatively regulates DNA double-strand break (DSB) repair. This involves HDAC6 degradation, promoting repair factor recruitment and DNA repair, offering a potential cancer therapy strategy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Histone deacetylase 6 (HDAC6) is known to regulate DNA damage signaling pathways.
  • Its role in DNA double-strand break (DSB) repair remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of HDAC6 in DNA double-strand break (DSB) repair.
  • To elucidate the molecular mechanisms by which HDAC6 influences DSB repair.

Main Methods:

  • Cellular assays to examine protein interactions and localization.
  • Ubiquitination and proteasomal degradation studies.
  • Assessment of DNA repair factor recruitment and DNA repair efficiency.

Main Results:

  • HDAC6 negatively regulates DSB repair in an enzyme activity-independent manner.
  • HDAC6 prevents RNF168 from ubiquitinating H2A/H2A.X in unstressed cells.
  • DSBs trigger RNF168-mediated ubiquitination and degradation of HDAC6, facilitating H2A/H2A.X ubiquitination and recruitment of repair factors like 53BP1 and BRCA1.

Conclusions:

  • A novel HDAC6-RNF168 regulatory axis controls H2A/H2A.X ubiquitination status.
  • This axis is crucial for efficient DSB repair.
  • Targeting this axis could overcome cancer cell resistance to genotoxic damage, presenting a potential therapeutic strategy.

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