In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias

Cell Rep. 2017 May 2;19(5):928-938. doi: 10.1016/j.celrep.2017.04.032.


Mammalian DNA replication origins are "licensed" by the loading of DNA helicases, a reaction that is mediated by CDC6 and CDT1 proteins. After initiation of DNA synthesis, CDC6 and CDT1 are inhibited to prevent origin reactivation and DNA overreplication before cell division. CDC6 and CDT1 are highly expressed in many types of cancer cells, but the impact of their deregulated expression had not been investigated in vivo. Here, we have generated mice strains that allow the conditional overexpression of both proteins. Adult mice were unharmed by the individual overexpression of either CDC6 or CDT1, but their combined deregulation led to DNA re-replication in progenitor cells and lethal tissue dysplasias. This study offers mechanistic insights into the necessary cooperation between CDC6 and CDT1 for facilitation of origin reactivation and describes the physiological consequences of DNA overreplication.

Keywords: CDC6; CDT1; DNA replication; replication origin; tissue dysplasia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • DNA Replication*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Diarrhea, Infantile / genetics*
  • Diarrhea, Infantile / metabolism
  • Female
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Malabsorption Syndromes / genetics*
  • Malabsorption Syndromes / metabolism
  • Male
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Transgenes


  • CDC6 protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Ris2 protein, mouse

Supplementary concepts

  • Diarrhea 5, With Tufting Enteropathy, Congenital