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RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites.

In response to DNA damage, cells initiate complex signalling cascades leading to growth arrest and DNA repair. The recruitment of 53BP1 to damaged sites requires the activation of the ubiquitination cascade controlled by the E3 ubiquitin ligases RNF8 and RNF168, and methylation of histone H4 on lysine 20. However, molecular events that regulate the accessibility of methylated histones, to allow the recruitment of 53BP1 to DNA breaks, are unclear. Here, we show that like 53BP1, the JMJD2A (also known as KDM4A) tandem tudor domain binds dimethylated histone H4K20; however, JMJD2A is degraded by the proteasome following the DNA damage in an RNF8-dependent manner. We demonstrate that JMJD2A is ubiquitinated by RNF8 and RNF168. Moreover, ectopic expression of JMJD2A abrogates 53BP1 recruitment to DNA damage sites, indicating a role in antagonizing 53BP1 for methylated histone marks. The combined knockdown of JMJD2A and JMJD2B significantly rescued the ability of RNF8- and RNF168-deficient cells to form 53BP1 foci. We propose that the RNF8-dependent degradation of JMJD2A regulates DNA repair by controlling the recruitment of 53BP1 at DNA damage sites.

Pubmed ID: 22373579


  • Mallette FA
  • Mattiroli F
  • Cui G
  • Young LC
  • Hendzel MJ
  • Mer G
  • Sixma TK
  • Richard S


The EMBO journal

Publication Data

April 18, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: CA132878
  • Agency: Canadian Institutes of Health Research, Id: MOP-67070
  • Agency: NCI NIH HHS, Id: R01 CA132878
  • Agency: NCI NIH HHS, Id: R01 CA132878-03
  • Agency: NCI NIH HHS, Id: R01 CA132878-04

Mesh Terms

  • Amino Acid Sequence
  • Cell Line
  • DNA
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins
  • Histones
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • Lysine
  • Methylation
  • Models, Biological
  • Molecular Sequence Data
  • Protein Binding
  • Signal Transduction
  • Ubiquitin-Protein Ligases