title: 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.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; ofernandez@cnio.es ajlopez@sund.ku.dk.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Lopez-Contreras
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
authors.forename: Julia
authors.initials: J
authors.lastname: Specks
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Jacqueline H
authors.initials: JH
authors.lastname: Barlow
authors.affiliation: Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
authors.forename: Chiara
authors.initials: C
authors.lastname: Ambrogio
authors.affiliation: Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark;
authors.forename: Claus
authors.initials: C
authors.lastname: Desler
authors.affiliation: Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden;
authors.forename: Svante
authors.initials: S
authors.lastname: Vikingsson
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
authors.forename: Sara
authors.initials: S
authors.lastname: Rodrigo-Perez
authors.affiliation: Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, SE-581 85 Linköping, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Green
authors.affiliation: Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark;
authors.forename: Lene Juel
authors.initials: LJ
authors.lastname: Rasmussen
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; ofernandez@cnio.es ajlopez@sund.ku.dk.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D019457:Chromosome Breakage; D043283:Chromosome Fragile Sites / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D008136:Longevity / Q000235:genetics*; D051379:Mice; D009705:Nucleosides / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D009705:Nucleosides; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D017346:Protein Serine-Threonine Kinases
keywords: ATR; RNR; fragile site; mouse models; replication stress
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