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

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.

SUBMITTER: Lopez-Contreras AJ

PROVIDER: S-EPMC4387711 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Lopez-Contreras Andres J AJ Specks Julia J Barlow Jacqueline H JH Ambrogio Chiara C Desler Claus C Vikingsson Svante S Rodrigo-Perez Sara S Green Henrik H Rasmussen Lene Juel LJ Murga Matilde M Nussenzweig André A Fernandez-Capetillo Oscar O

Genes & development 20150401 7

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 ...[more]

PMID: 25838540

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