Journal
JOURNAL OF CELL SCIENCE
Volume 129, Issue 16, Pages 3167-3177Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.187781
Keywords
Cytidine deaminase; Nucleotide pool; PARP-1; Chk1; Ultrafine anaphase bridges
Categories
Funding
- Institut Curie [grant PICSysBio]
- Centre National de la Recherche Scientifique (CNRS)
- Ligue Contre le Cancer (Comite de l'Essonne)
- Association pour la Recherche sur le Cancer (ARC) [SFI20121205645]
- Agence Nationale de la Recherche [ANR-14-CE14-0004-01]
- Ministere de l'Education Nationale, de l'Enseignement Superieur et de la Recherche
- Association pour la Recherche sur le Cancer [DOC20140601310]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE14-0004] Funding Source: Agence Nationale de la Recherche (ANR)
Ask authors/readers for more resources
Cytidine deaminase (CDA) deficiency induces an excess of cellular dCTP, which reduces basal PARP-1 activity, thereby compromising complete DNA replication, leading to ultrafine anaphase bridge (UFB) formation. CDA dysfunction has pathological implications, notably in cancer and in Bloom syndrome. It remains unknown how reduced levels of PARP-1 activity and pyrimidine pool imbalance lead to the accumulation of unreplicated DNA during mitosis. We report that a decrease in PARP-1 activity in CDA-deficient cells impairs DNA-damage-induced Chk1 activation, and, thus, the downstream checkpoints. Chemical inhibition of the ATR-Chk1 pathway leads to UFB accumulation, and we found that this pathway was compromised in CDA-deficient cells. Our data demonstrate that ATR-Chk1 acts downstream from PARP-1, preventing the accumulation of unreplicated DNA in mitosis, and, thus, UFB formation. Finally, delaying entry into mitosis is sufficient to prevent UFB formation in both CDA-deficient and CDA-proficient cells, suggesting that both physiological and pathological UFBs are derived from unreplicated DNA. Our findings demonstrate an unsuspected requirement for a balanced nucleotide pool for optimal Chk1 activation both in unchallenged cells and in response to genotoxic stress.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available