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

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. A.J.L.-C. and C.A. were funded a post-doctoral fellowship from the Spanish Association for Cancer Research (AECC). J.S. is a recipient of a predoctoral fellowship from the Spanish government (BES-2012-05 2030). S.V. and H.G. are funded by the Swedish Research Council and the Swedish Cancer Society. Work in O.F.-C.'s laboratory was supported by Fundacion Botin, Banco Santander through its Santander Universities Global Division, and grants from Ministerio de Economia y Competitividad (MINECO; SAF2011-23753), Worldwide Cancer Research (12-0229), Fundacio La Marato de TV3, Howard Hughes Medical Institute, and the European Research Council (ERC-617840). Work in A.J.L.-C.'s laboratory is funded by the Danish Council for Independent Research (DFF) and the Danish National Research Foundatio Sí