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JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks

Sugiko Watanabe1, Kenji Watanabe, Vyacheslav Akimov

  • 11] Danish Cancer Society Research Center, Copenhagen, Denmark. [2] [3].

Nature Structural & Molecular Biology
|November 19, 2013
PubMed

Insights

The demethylase JMJD1C regulates DNA repair by interacting with RNF8 and MDC1, influencing the RAP80-BRCA1 pathway. Its depletion impacts DNA repair, potentially affecting cancer treatment strategies.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • DNA double-strand breaks (DSBs) trigger repair pathways involving ubiquitylation.
  • RNF8 and RNF168 ubiquitin ligases mediate chromatin ubiquitylation, recruiting 53BP1 or RAP80-BRCA1.
  • The precise role of specific regulators in these pathways is under investigation.

Purpose of the Study:

  • To investigate the role of human demethylase JMJD1C in the DNA-damage response (DDR).
  • To elucidate the mechanism by which JMJD1C influences DSB repair pathways.

Main Methods:

  • Assessed JMJD1C stabilization, recruitment to DSBs, and requirement for ubiquitylation and factor recruitment.
  • Utilized co-immunoprecipitation to study interactions between JMJD1C, RNF8, and MDC1.
  • Investigated JMJD1C's demethylase activity on MDC1 and its effect on downstream events.
  • Analyzed the impact of JMJD1C depletion on RAD51 foci formation and cellular response to genotoxic agents.

Main Results:

  • JMJD1C is stabilized by RNF8, recruited to DSBs, and promotes RAP80-BRCA1 recruitment but not 53BP1.
  • JMJD1C demethylates MDC1 at Lys45, enhancing MDC1-RNF8 interaction and RNF8-dependent MDC1 ubiquitylation.
  • JMJD1C restricts RAD51 foci formation.
  • JMJD1C depletion confers resistance to ionizing radiation and PARP inhibitors.

Conclusions:

  • JMJD1C is a novel component of the DNA-damage response pathway, specifically regulating the RAP80-BRCA1 branch.
  • JMJD1C's function in DNA repair has implications for maintaining genome integrity.
  • Aberrant JMJD1C levels in cancer suggest its potential as a therapeutic target for improving cancer treatment outcomes.

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