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HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes.

Regulatory ubiquitylation is emerging as an important mechanism to protect genome integrity in cells exposed to DNA damage. However, the spectrum of known ubiquitin regulators of the DNA damage response (DDR) is limited and their functional interplay is poorly understood. Here, we identify HERC2 as a factor that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes. In response to ionising radiation (IR), HERC2 forms a complex with RNF8, a ubiquitin ligase involved in the DDR. The HERC2-RNF8 interaction requires IR-inducible phosphorylation of HERC2 at Thr 4827, which in turn binds to the forkhead-associated (FHA) domain of RNF8. Mechanistically, we provide evidence that HERC2 facilitates assembly of the ubiquitin-conjugating enzyme Ubc13 with RNF8, thereby promoting DNA damage-induced formation of Lys 63-linked ubiquitin chains. We also show that HERC2 interacts with, and maintains the levels of, RNF168, another ubiquitin ligase operating downstream of RNF8 (Refs 7, 8). Consequently, knockdown of HERC2 abrogates ubiquitin-dependent retention of repair factors such as 53BP1, RAP80 and BRCA1. Together with the increased radiosensitivity of HERC2-depleted cells, these results uncover a regulatory layer in the orchestration of protein interactions on damaged chromosomes and they underscore the role of ubiquitin-mediated signalling in genome maintenance.

Pubmed ID: 20023648

Authors

  • Bekker-Jensen S
  • Rendtlew Danielsen J
  • Fugger K
  • Gromova I
  • Nerstedt A
  • Lukas C
  • Bartek J
  • Lukas J
  • Mailand N

Journal

Nature cell biology

Publication Data

January 22, 2010

Associated Grants

None

Mesh Terms

  • BRCA1 Protein
  • Bone Neoplasms
  • Carrier Proteins
  • Cells, Cultured
  • Chromosomes, Human
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kidney
  • Lysine
  • Mutation
  • Nuclear Proteins
  • Osteosarcoma
  • Phosphorylation
  • RNA, Small Interfering
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Ultraviolet Rays