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

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

doi:10.1101/gad.256958.114

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

¹Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
²Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
³Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
⁴Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark;
⁵Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden;
⁶Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, SE-581 85 Linköping, Sweden

Corresponding authors: ofernandez{at}cnio.es, ajlopez{at}sund.ku.dk

↵8 These authors contributed equally to this work.

↵7 Present address: Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.

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.

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Footnotes

Supplemental material is available for this article.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.256958.114.

Received December 5, 2014.
Accepted March 2, 2015.

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