Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression

Mol Cell. 2011 Mar 4;41(5):543-53. doi: 10.1016/j.molcel.2011.02.006.


Eukaryotic cells license far more origins than are actually used for DNA replication, thereby generating a large number of dormant origins. Accumulating evidence suggests that such origins play a role in chromosome stability and tumor suppression, though the underlying mechanism is largely unknown. Here, we show that a loss of dormant origins results in an increased number of stalled replication forks, even in unchallenged S phase in primary mouse fibroblasts derived from embryos homozygous for the Mcm4(Chaos3) allele. We found that this allele reduces the stability of the MCM2-7 complex, but confers normal helicase activity in vitro. Despite the activation of multiple fork recovery pathways, replication intermediates in these cells persist into M phase, increasing the number of abnormal anaphase cells with lagging chromosomes and/or acentric fragments. These findings suggest that dormant origins constitute a major pathway for stalled fork recovery, contributing to faithful chromosome segregation and tumor suppression.

Publication types

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

MeSH terms

  • Alleles
  • Anaphase
  • Animals
  • Cell Cycle
  • Cell Division
  • Chromosomal Instability
  • Chromosome Segregation
  • Cytokinesis
  • DNA Helicases / metabolism
  • DNA Replication
  • Fibroblasts / cytology
  • Mice
  • Neoplasms / pathology*
  • Rad51 Recombinase / metabolism
  • Recombination, Genetic
  • S Phase*


  • Rad51 Recombinase
  • Rad51 protein, mouse
  • DNA Helicases