MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

Genes Dev. 2015 Sep 15;29(18):1955-68. doi: 10.1101/gad.264192.115. Epub 2015 Sep 3.

Abstract

MERIT40 is an essential component of the RAP80 ubiquitin recognition complex that targets BRCA1 to DNA damage sites. Although this complex is required for BRCA1 foci formation, its physiologic role in DNA repair has remained enigmatic, as has its relationship to canonical DNA repair mechanisms. Surprisingly, we found that Merit40(-/-) mice displayed marked hypersensitivity to DNA interstrand cross-links (ICLs) but not whole-body irradiation. MERIT40 was rapidly recruited to ICL lesions prior to FANCD2, and Merit40-null cells exhibited delayed ICL unhooking coupled with reduced end resection and homologous recombination at ICL damage. Interestingly, Merit40 mutation exacerbated ICL-induced chromosome instability in the context of concomitant Brca2 deficiency but not in conjunction with Fancd2 mutation. These findings implicate MERIT40 in the earliest stages of ICL repair and define specific functional interactions between RAP80 complex-dependent ubiquitin recognition and the Fanconi anemia (FA)-BRCA ICL repair network.

Keywords: BRCA2; DNA2; MERIT40; interstrand cross-link repair; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • BRCA2 Protein / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Chromosomal Instability / genetics
  • DNA Damage
  • DNA Helicases / metabolism
  • DNA Repair / genetics*
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / metabolism
  • Histone Chaperones
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Protein Transport
  • Transcription Factors / metabolism
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • BRCA2 Protein
  • BRCA2 protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Fancd2 protein, mouse
  • Fanconi Anemia Complementation Group D2 Protein
  • Histone Chaperones
  • MERIT40 protein, mouse
  • Rap80 protein, mouse
  • Transcription Factors
  • DNA Helicases