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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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.

Original languageEnglish
JournalGenes & Development
Volume29
Issue number7
Pages (from-to)690-5
Number of pages6
ISSN0890-9369
DOIs
Publication statusPublished - 1 Apr 2015

ID: 135739326