Structural insights into the functions of the FANCM-FAAP24 complex in DNA repair

Nucleic Acids Res. 2013 Dec;41(22):10573-83. doi: 10.1093/nar/gkt788. Epub 2013 Sep 3.

Abstract

Fanconi anemia (FA) is a genetically heterogeneous disorder associated with deficiencies in the FA complementation group network. FA complementation group M (FANCM) and FA-associated protein 24 kDa (FAAP24) form a stable complex to anchor the FA core complex to chromatin in repairing DNA interstrand crosslinks. Here, we report the first crystal structure of the C-terminal segment of FANCM in complex with FAAP24. The C-terminal segment of FANCM and FAAP24 both consist of a nuclease domain at the N-terminus and a tandem helix-hairpin-helix (HhH)2 domain at the C-terminus. The FANCM-FAAP24 complex exhibits a similar architecture as that of ApXPF. However, the variations of several key residues and the electrostatic property at the active-site region render a catalytically inactive nuclease domain of FANCM, accounting for the lack of nuclease activity. We also show that the first HhH motif of FAAP24 is a potential binding site for DNA, which plays a critical role in targeting FANCM-FAAP24 to chromatin. These results reveal the mechanistic insights into the functions of FANCM-FAAP24 in DNA repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • DNA / metabolism
  • DNA Helicases / chemistry*
  • DNA Helicases / metabolism
  • DNA Repair
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • Fanconi Anemia Complementation Group Proteins
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Protein Interaction Domains and Motifs

Substances

  • DNA-Binding Proteins
  • FAAP24 protein, human
  • Fanconi Anemia Complementation Group Proteins
  • DNA
  • FANCM protein, human
  • DNA Helicases

Associated data

  • PDB/4M6W