Format

Send to

Choose Destination
Genes Dev. 2015 Apr 1;29(7):690-5. doi: 10.1101/gad.256958.114.

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

Author information

1
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; ofernandez@cnio.es ajlopez@sund.ku.dk.
2
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
3
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
4
Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
5
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark;
6
Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden;
7
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.

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.

KEYWORDS:

ATR; RNR; fragile site; mouse models; replication stress

PMID:
25838540
PMCID:
PMC4387711
DOI:
10.1101/gad.256958.114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center