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Article Dans Une Revue Journal of Cell Science Année : 2016

A balanced pyrimidine pool is required for optimal Chk1 activation to prevent ultrafine anaphase bridge formation

Résumé

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 DNAdamage-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.
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Dates et versions

hal-02345992 , version 1 (06-12-2020)

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Simon Gemble, Géraldine Buhagiar-Labarchède, Rosine Onclercq-Delic, Denis Biard, Sarah Lambert, et al.. A balanced pyrimidine pool is required for optimal Chk1 activation to prevent ultrafine anaphase bridge formation. Journal of Cell Science, 2016, 129 (16), pp.3167-3177. ⟨10.1242/jcs.187781⟩. ⟨hal-02345992⟩
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