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 Madsen; 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

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

37 Citations (Scopus)

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.

Original language	English
Journal	Genes & Development
Volume	29
Issue number	7
Pages (from-to)	690-5
Number of pages	6
ISSN	0890-9369
DOIs	https://doi.org/10.1101/gad.256958.114
Publication status	Published - 1 Apr 2015

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Lopez-Contreras, A. J., Specks, J., Barlow, J. H., Ambrogio, C., Madsen, C. D., Vikingsson, S., Rodrigo-Perez, S., Green, H., Rasmussen, L. J., Murga, M., Nussenzweig, A., & Fernandez-Capetillo, O. (2015). Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice. Genes & Development, 29(7), 690-5. https://doi.org/10.1101/gad.256958.114

Lopez-Contreras, AJ, Specks, J, Barlow, JH, Ambrogio, C, Madsen, CD, Vikingsson, S, Rodrigo-Perez, S, Green, H, Rasmussen, LJ, Murga, M, Nussenzweig, A & Fernandez-Capetillo, O 2015, 'Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice', Genes & Development, vol. 29, no. 7, pp. 690-5. https://doi.org/10.1101/gad.256958.114

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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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doi = "10.1101/gad.256958.114",

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AU - Lopez-Contreras, Andres J

AU - Specks, Julia

AU - Barlow, Jacqueline H

AU - Ambrogio, Chiara

AU - Madsen, Claus Desler

AU - Vikingsson, Svante

AU - Rodrigo-Perez, Sara

AU - Green, Henrik

AU - Rasmussen, Lene Juel

AU - Murga, Matilde

AU - Nussenzweig, André

AU - Fernandez-Capetillo, Oscar

PY - 2015/4/1

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N2 - 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.

AB - 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.

U2 - 10.1101/gad.256958.114

DO - 10.1101/gad.256958.114

M3 - Journal article

C2 - 25838540

SN - 0890-9369

VL - 29

SP - 690

EP - 695

JO - Genes & Development

JF - Genes & Development

IS - 7

ER -

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

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