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

Andres J. Lopez-Contreras, Julia Specks, Jacqueline Barlow, Chiara Ambrogio, Claus Desler, Svante Vikingsson, Sara Rodrigo-Perez, Henrik Green, Lene Juel Rasmussen, Matilde Murga, André Nussenzweig, Oscar Fernandez-Capetillo

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30 Scopus citations

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 (Rrm2TG) 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.

Original languageEnglish (US)
Pages (from-to)690-695
Number of pages6
JournalGenes and Development
Volume29
Issue number7
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Keywords

  • ATR
  • Fragile site
  • Mouse models
  • Replication stress
  • RNR

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Lopez-Contreras, A. J., Specks, J., Barlow, J., Ambrogio, C., Desler, C., Vikingsson, S., Rodrigo-Perez, S., Green, H., Rasmussen, L. J., Murga, M., Nussenzweig, A., & Fernandez-Capetillo, O. (2015). Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice. Genes and Development, 29(7), 690-695. https://doi.org/10.1101/gad.256958.114