Pyrimidine Pool Disequilibrium Induced by a Cytidine Deaminase Deficiency Inhibits PARP-1 Activity, Leading to the Under Replication of DNA

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The maintenance of genome stability is essential for the accurate transmission of genetic information, to ensure the successful duplication of chromosomes and their even segregation during mitosis. Errors occurring during DNA replication may affect both the accuracy of chromosome duplication and the balance of chromosome segregation during mitosis. Accurate DNA replication is strongly dependent on deoxynucleotides (dNTP) concentrations. Distortions in dNTP pool affect the rate of replication fork progression and compromise genetic stability. In the work presented here, we identified a novel mechanism by which dNTP pool disequilibrium compromises the completion of DNA replication and thus chromosome segregation, independently of the rate of fork progression. This mechanism involves the intracellular accumulation of deoxycytidine due to cytidine deaminase (CDA) deficiency, inhibiting PARP-1 activity. These results have direct implications for Bloom syndrome (BS), a rare genetic disease combining susceptibility to cancer and genomic instability. BS cells also have a CDA defect, resulting in a high frequency of ultrafine anaphase bridges due entirely to dCTP-dependent PARP-1 inhibition. These data highlight new pathological consequences of the distortion of dNTP pools and reveal an unexpected role for PARP-1 in preventing the accumulation of excessive amounts of unreplicated DNA and chromosome segregation defects.

Vyšlo v časopise: Pyrimidine Pool Disequilibrium Induced by a Cytidine Deaminase Deficiency Inhibits PARP-1 Activity, Leading to the Under Replication of DNA. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005384
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005384

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