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Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice
Spanish National Cancer Research Centre CNIO, Spain.
Spanish National Cancer Research Centre CNIO, Spain.
NCI, MD 20892 USA.
Spanish National Cancer Research Centre CNIO, Spain.
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2015 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 29, no 7, 690-695 p.Article in journal (Refereed) Published
Abstract [en]

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. Supplemental material is available for this article.

Place, publisher, year, edition, pages
Cold Spring Harbor Laboratory Press , 2015. Vol. 29, no 7, 690-695 p.
Keyword [en]
ATR; fragile site; mouse models; RNR; replication stress
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-118056DOI: 10.1101/gad.256958.114ISI: 000352161600002PubMedID: 25838540OAI: diva2:812905

Funding Agencies|Spanish Association for Cancer Research (AECC); Spanish government [BES-2012-05 2030]; Swedish Research Council; Swedish Cancer Society; Fundacion Botin; Banco Santander through its Santander Universities Global Division; Ministerio de Economia y Competitividad (MINECO) [SAF2011-23753]; Worldwide Cancer Research [12-0229]; Fundacio La Marato de TV3; Howard Hughes Medical Institute; European Research Council [ERC-617840]; Danish Council for Independent Research (DFF); Danish National Research Foundation

Available from: 2015-05-20 Created: 2015-05-20 Last updated: 2015-05-26

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