Gemble S Ahuja A Buhagiar-Labarchède G Onclercq-Delic R Dairou J Biard DS Lambert S Lopes M Amor-Guéret M 2015 Genome stability is jeopardized by imbalances of the dNTP pool; such imbalances affect the rate of fork progression. For example, cytidine deaminase (CDA) deficiency leads to an excess of dCTP, slowing the replication fork. We describe here a novel mechanism by which pyrimidine pool disequilibrium compromises the completion of replication and chromosome segregation: the intracellular accumulation of dCTP inhibits PARP-1 activity. CDA deficiency results in incomplete DNA replication when cells enter mitosis, leading to the formation of ultrafine anaphase bridges between sister-chromatids at "difficult-to-replicate" sites such as centromeres and fragile sites. Using molecular combing, electron microscopy and a sensitive assay involving cell imaging to quantify steady-state PAR levels, we found that DNA replication was unsuccessful due to the partial inhibition of basal PARP-1 activity, rather than slower fork speed. The stimulation of PARP-1 activity in CDA-deficient cells restores replication and, thus, chromosome segregation. Moreover, increasing intracellular dCTP levels generates under-replication-induced sister-chromatid bridges as efficiently as PARP-1 knockdown. These results have direct implications for Bloom syndrome (BS), a rare genetic disease combining susceptibility to cancer and genomic instability. BS results from mutation of the BLM gene, encoding BLM, a RecQ 3'-5' DNA helicase, a deficiency of which leads to CDA downregulation. BS cells thus have a CDA defect, resulting in a high frequency of ultrafine anaphase bridges due entirely to dCTP-dependent PARP-1 inhibition and independent of BLM status. Our study describes previously unknown pathological consequences of the distortion of dNTP pools and reveals an unexpected role for PARP-1 in preventing DNA under-replication and chromosome segregation defects. application/pdf https://sonar.ch/global/documents/298492 eng info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pgen.1005384 info:eu-repo/semantics/altIdentifier/pmid/26181065 info:eu-repo/semantics/openAccess PLoS genetics. - 2015 Bloom Syndrome Cell Line Centromere Chromosome Fragile Sites Chromosome Segregation Cytidine Deaminase DNA Replication Genomic Instability Humans Mitosis Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases Pyrimidines RecQ Helicases Sister Chromatid Exchange Pyrimidine Pool Disequilibrium Induced by a Cytidine Deaminase Deficiency Inhibits PARP-1 Activity, Leading to the Under Replication of DNA. http://purl.org/coar/resource_type/c_6501