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USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response

Zhiquan Wang1, Honglian Zhang1, Ji Liu1

  • 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA;

Genes & Development
|April 17, 2016
PubMed

Insights

USP51, a novel deubiquitylating enzyme (DUB), removes histone H2AK13,15ub marks at DNA double-strand breaks. USP51 regulates DNA damage response and genome stability by controlling the dynamic assembly of repair proteins.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Dynamic regulation of histone ubiquitylation is critical for DNA repair and genome stability.
  • Histone H2A Lys13,15 ubiquitylation (H2AK13,15ub) is mediated by RNF168 at DNA double-strand breaks (DSBs).
  • The deubiquitylating enzyme (DUB) responsible for removing H2AK13,15ub has not been identified.

Purpose of the Study:

  • To identify the DUB that removes H2AK13,15ub.
  • To investigate the role of this DUB in DNA damage response and genome stability.

Main Methods:

  • Depletion and overexpression of USP51 in human cells.
  • Analysis of DNA damage foci (53BP1, BRCA1, RNF168).
  • In vitro deubiquitylation assays using purified proteins.
  • Chromatin recruitment assays post-DNA damage.

Main Results:

  • USP51 was identified as a DUB that deubiquitylates H2AK13,15ub.
  • USP51 depletion led to increased spontaneous DNA damage, elevated H2AK15ub levels, and impaired DNA damage response.
  • USP51 overexpression suppressed ionizing radiation-induced 53BP1 and BRCA1 foci formation, functioning downstream of RNF168.
  • USP51 directly binds H2A-H2B and deubiquitylates H2AK13,15ub in vitro.
  • USP51 is recruited to chromatin after DNA damage and regulates 53BP1 and BRCA1 foci dynamics.

Conclusions:

  • USP51 is the primary DUB responsible for removing H2AK13,15ub.
  • USP51 plays a crucial role in regulating the DNA damage response pathway.
  • USP51's function is essential for maintaining genome stability by controlling DNA repair protein dynamics.
Keywords:
DNA damage responseH2AK15ubUSP51deubiqutylating enzyme

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