Cytidine deaminase deficiency impairs sister chromatid disjunction by decreasing PARP-1 activity |
| |
Authors: | Simon Gemble Géraldine Buhagiar-Labarchède Rosine Onclercq-Delic Christian Jaulin |
| |
Institution: | 1. Institut Curie, PSL Research University, UMR 3348, Unité Stress Génotoxiques et Cancer, Centre de Recherche, Orsay, France;2. CNRS UMR 3348, Centre Universitaire, Orsay, France;3. Université Paris Sud, Université Paris Saclay, UMR3348, Centre Universitaire d'Orsay, France;4. Institut de Génétique et Développement de Rennes, Equipe Epigénétique et Cancer, UMR 6290 CNRS, Université Rennes 1, Rennes Cedex, France |
| |
Abstract: | Bloom Syndrome (BS) is a rare genetic disease characterized by high levels of chromosomal instability and an increase in cancer risk. Cytidine deaminase (CDA) expression is downregulated in BS cells, leading to an excess of cellular dC and dCTP that reduces basal PARP-1 activity, compromising optimal Chk1 activation and reducing the efficiency of downstream checkpoints. This process leads to the accumulation of unreplicated DNA during mitosis and, ultimately, ultrafine anaphase bridge (UFB) formation. BS cells also display incomplete sister chromatid disjunction when depleted of cohesin. Using a combination of fluorescence in situ hybridization and chromosome spreads, we investigated the possible role of CDA deficiency in the incomplete sister chromatid disjunction in cohesin-depleted BS cells. The decrease in basal PARP-1 activity in CDA-deficient cells compromised sister chromatid disjunction in cohesin-depleted cells, regardless of BLM expression status. The observed incomplete sister chromatid disjunction may be due to the accumulation of unreplicated DNA during mitosis in CDA-deficient cells, as reflected in the changes in centromeric DNA structure associated with the decrease in basal PARP-1 activity. Our findings reveal a new function of PARP-1 in sister chromatid disjunction during mitosis. |
| |
Keywords: | chromosome segregation cytidine deaminase mitosis nucleotide pool PARP-1 sister chromatid disjunction |
|
|