Dormant origins, the licensing checkpoint, and the response to replicative stresses

Cold Spring Harb Perspect Biol. 2012 Oct 1;4(10):a012955. doi: 10.1101/cshperspect.a012955.


Only ∼10% of replication origins that are licensed by loading minichromosome maintenance 2-7 (MCM2-7) complexes are normally used, with the majority remaining dormant. If replication fork progression is inhibited, nearby dormant origins initiate to ensure that all of the chromosomal DNA is replicated. At the same time, DNA damage-response kinases are activated, which preferentially suppress the assembly of new replication factories. This diverts initiation events away from completely new areas of the genome toward regions experiencing replicative stress. Mice hypomorphic for MCM2-7, which activate fewer dormant origins in response to replication inhibition, are cancer-prone and are genetically unstable. The licensing checkpoint delays entry into S phase if an insufficient number of origins have been licensed. In contrast, humans with Meier-Gorlin syndrome have mutations in pre-RC proteins and show defects in cell proliferation that may be a consequence of chronic activation of the licensing checkpoint.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology
  • Congenital Microtia
  • DNA Damage
  • DNA Replication / physiology*
  • Ear / abnormalities
  • Growth Disorders / genetics
  • Humans
  • Mice
  • Micrognathism / genetics
  • Models, Genetic*
  • Patella / abnormalities
  • Replication Origin / genetics
  • Replication Origin / physiology*
  • Stress, Physiological


  • Cell Cycle Proteins

Supplementary concepts

  • Meier-Gorlin syndrome