PP2A licenses the FANCD2/FANCI complex for chromosome loading

Cell Rep. 2024 Nov 26;43(11):114971. doi: 10.1016/j.celrep.2024.114971. Epub 2024 Nov 12.

Abstract

The Fanconi anemia (FA) pathway removes interstrand crosslinks (ICLs) between the Watson-Crick strands of the DNA double helix in humans. Central to the pathway is the FANCD2/FANCI complex, which must be loaded onto chromosomes. Here, we report the identification of a PP2A phosphatase complex, which specifically dephosphorylates an inhibitory cluster in FANCD2, thereby licensing its loading in response to DNA damage. We show that PP2A is required for normal monoubiquitination of the FANCD2/FANCI complex and for its loading onto chromosomes. We have fully reconstituted a coupled dephosphorylation-ubiquitination reaction in vitro using a highly purified PP2A complex. Using super-resolution live-cell single-molecule tracking, we show how PP2A switches on the FA pathway in response to ICLs and that cells are sensitive to ICL-forming drugs in the absence of PP2A. Our work uncovers a mechanism where PP2A facilitates the activation of the FA pathway by licensing chromosome loading of the FANCD2/FANCI complex.

Keywords: CP: Molecular biology; DNA interstrand crosslink repair; FANCD2; FANCD2/FANCI complex; Fanconi anemia; ICL repair; PP2A; dephosphorylation; genome stability; phosphorylation.

MeSH terms

  • Chromosomes, Human / metabolism
  • DNA Damage
  • Fanconi Anemia Complementation Group D2 Protein* / genetics
  • Fanconi Anemia Complementation Group D2 Protein* / metabolism
  • Fanconi Anemia Complementation Group Proteins / genetics
  • Fanconi Anemia Complementation Group Proteins / metabolism
  • HeLa Cells
  • Humans
  • Phosphorylation
  • Protein Phosphatase 2* / metabolism
  • Ubiquitination

Substances

  • Fanconi Anemia Complementation Group D2 Protein
  • Protein Phosphatase 2
  • FANCD2 protein, human
  • FANCI protein, human
  • Fanconi Anemia Complementation Group Proteins