Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome

Pauline Chabosseau, Géraldine Buhagiar-Labarchède, Rosine Onclercq-Delic, Sarah Lambert, Michelle Debatisse, Olivier Brison and Mounira Amor-Guéret ()
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Pauline Chabosseau: Institut Curie, Centre de Recherche
Géraldine Buhagiar-Labarchède: Institut Curie, Centre de Recherche
Rosine Onclercq-Delic: Institut Curie, Centre de Recherche
Sarah Lambert: Institut Curie, Centre de Recherche
Michelle Debatisse: CNRS UMR 3244, Institut Curie, Centre de Recherche
Olivier Brison: CNRS UMR 3244, Institut Curie, Centre de Recherche
Mounira Amor-Guéret: Institut Curie, Centre de Recherche

Nature Communications, 2011, vol. 2, issue 1, 1-6

Abstract: Abstract Defects in DNA replication are associated with genetic instability and cancer development, as illustrated in Bloom syndrome. Features of this syndrome include a slowdown in replication speed, defective fork reactivation and high rates of sister chromatid exchange, with a general predisposition to cancer. Bloom syndrome is caused by mutations in the BLM gene encoding a RecQ helicase. Here we report that BLM deficiency is associated with a strong cytidine deaminase defect, leading to pyrimidine pool disequilibrium. In BLM-deficient cells, pyrimidine pool normalization leads to reduction of sister chromatid exchange frequency and is sufficient for full restoration of replication fork velocity but not the fork restart defect, thus identifying the part of the Bloom syndrome phenotype because of pyrimidine pool imbalance. This study provides new insights into the molecular basis of control of replication speed and the genetic instability associated with Bloom syndrome. Nucleotide pool disequilibrium could be a general phenomenon in a large spectrum of precancerous and cancer cells.

Date: 2011
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DOI: 10.1038/ncomms1363

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