title: Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome.
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.
authors.affiliation: Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chabosseau
authors.forename: Géraldine
authors.initials: G
authors.lastname: Buhagiar-Labarchède
authors.forename: Rosine
authors.initials: R
authors.lastname: Onclercq-Delic
authors.forename: Sarah
authors.initials: S
authors.lastname: Lambert
authors.forename: Michelle
authors.initials: M
authors.lastname: Debatisse
authors.forename: Olivier
authors.initials: O
authors.lastname: Brison
authors.forename: Mounira
authors.initials: M
authors.lastname: Amor-Guéret
mesh_terms: D001816:Bloom Syndrome / Q000235:genetics*; D015153:Blotting, Western; D002460:Cell Line; D003564:Cytidine Deaminase / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D046228:Microarray Analysis; D016297:Mutagenesis, Site-Directed; D011743:Pyrimidines / Q000378:metabolism*; D053484:RecQ Helicases / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012854:Sister Chromatid Exchange / Q000235:genetics; D018709:Statistics, Nonparametric
chemical_list: D017931:DNA Primers; D011743:Pyrimidines; D003564:Cytidine Deaminase; C097151:Bloom syndrome protein; D053484:RecQ Helicases