Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice

Genes Dev. 2015 Apr 1;29(7):690-5. doi: 10.1101/gad.256958.114.

Abstract

In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.

Keywords: ATR; RNR; fragile site; mouse models; replication stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival
  • Cells, Cultured
  • Chromosome Breakage*
  • Chromosome Fragile Sites / genetics*
  • Enzyme Activation / genetics
  • Fibroblasts / cytology
  • Gene Dosage / genetics*
  • Humans
  • Longevity / genetics*
  • Mice
  • Nucleosides / metabolism
  • Protein Serine-Threonine Kinases / genetics*
  • Ribonucleoside Diphosphate Reductase / genetics*
  • Survival Analysis

Substances

  • Nucleosides
  • ribonucleotide reductase M2
  • Ribonucleoside Diphosphate Reductase
  • Protein Serine-Threonine Kinases