The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair

Science. 2009 Dec 18;326(5960):1698-701. doi: 10.1126/science.1182372. Epub 2009 Nov 12.

Abstract

Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.

Publication types

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

MeSH terms

  • Animals
  • Cell-Free System
  • Chromatin / metabolism
  • DNA / biosynthesis
  • DNA Damage
  • DNA Repair*
  • DNA Replication*
  • Fanconi Anemia / genetics
  • Fanconi Anemia / metabolism
  • Fanconi Anemia Complementation Group D2 Protein / metabolism*
  • Fanconi Anemia Complementation Group Proteins / metabolism*
  • Molecular Sequence Data
  • Recombinant Proteins / metabolism
  • S Phase
  • Signal Transduction
  • Ubiquitinated Proteins / metabolism
  • Ubiquitination
  • Xenopus Proteins / metabolism*
  • Xenopus laevis

Substances

  • Chromatin
  • FANCI Protein, Xenopus
  • Fanconi Anemia Complementation Group D2 Protein
  • Fanconi Anemia Complementation Group Proteins
  • Recombinant Proteins
  • Ubiquitinated Proteins
  • Xenopus Proteins
  • DNA

Associated data

  • GENBANK/GU144566