ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress

Mol Cell. 2015 Apr 16;58(2):323-38. doi: 10.1016/j.molcel.2015.02.031. Epub 2015 Apr 2.

Abstract

Excess dormant origins bound by the minichromosome maintenance (MCM) replicative helicase complex play a critical role in preventing replication stress, chromosome instability, and tumorigenesis. In response to DNA damage, replicating cells must coordinate DNA repair and dormant origin firing to ensure complete and timely replication of the genome; how cells regulate this process remains elusive. Herein, we identify a member of the Fanconi anemia (FA) DNA repair pathway, FANCI, as a key effector of dormant origin firing in response to replication stress. Cells lacking FANCI have reduced number of origins, increased inter-origin distances, and slowed proliferation rates. Intriguingly, ATR-mediated FANCI phosphorylation inhibits dormant origin firing while promoting replication fork restart/DNA repair. Using super-resolution microscopy, we show that FANCI co-localizes with MCM-bound chromatin in response to replication stress. These data reveal a unique role for FANCI as a modulator of dormant origin firing and link timely genome replication to DNA repair.

Publication types

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

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Proliferation
  • Chromatin / metabolism*
  • DNA Damage*
  • DNA Replication*
  • Fanconi Anemia Complementation Group Proteins / genetics
  • Fanconi Anemia Complementation Group Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Hydroxyurea / pharmacology
  • Minichromosome Maintenance Proteins / genetics
  • Minichromosome Maintenance Proteins / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction

Substances

  • Cell Cycle Proteins
  • Chromatin
  • FANCI protein, human
  • Fanconi Anemia Complementation Group Proteins
  • CDC7 protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Minichromosome Maintenance Proteins
  • Hydroxyurea