Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation
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Damaged replication forks activate poly(ADP-ribose) polymerase 1 (PARP1), which catalyses poly(ADP-ribose) (PAR) formation; however, how PARP1 or poly(ADP-ribosyl)ation is involved in the S-phase checkpoint is unknown. Here we show that PAR, supplied by PARP1, interacts with Chk1 via a novel PAR-binding regulatory (PbR) motif in Chk1, independent of ATR and its activity. iPOND studies reveal that Chk1 associates readily with the unperturbed replication fork and that PAR is required for efficient retention of Chk1 and phosphorylated Chk1 at the fork. A PbR mutation, which disrupts PAR binding, but not the interaction with its partners Claspin or BRCA1, impairs Chk1 and the S-phase checkpoint activation, and mirrors Chk1 knockdown-induced hypersensitivity to fork poisoning. We find that long chains, but not short chains, of PAR stimulate Chk1 kinase activity. Collectively, we disclose a previously unrecognized mechanism of the S-phase checkpoint by PAR metabolism that modulates Chk1 activity at the replication fork.
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MIN, WooKee, Christopher BRUHN, Paulius GRIGARAVICIUS, Zhong-Wei ZHOU, Fu LI, Anja KRÜGER, Bénazir SIDDEEK, Karl-Otto GREULICH, Oliver POPP, Chris MEISEZAHL, Cornelis F. CALKHOVEN, Alexander BÜRKLE, Xingzhi XU, Zhao-Qi WANG, 2013. Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation. In: Nature Communications. 2013, 4, 2993. eISSN 2041-1723. Available under: doi: 10.1038/ncomms3993BibTex
@article{Min2013PolyA-26305, year={2013}, doi={10.1038/ncomms3993}, title={Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation}, volume={4}, journal={Nature Communications}, author={Min, WooKee and Bruhn, Christopher and Grigaravicius, Paulius and Zhou, Zhong-Wei and Li, Fu and Krüger, Anja and Siddeek, Bénazir and Greulich, Karl-Otto and Popp, Oliver and Meisezahl, Chris and Calkhoven, Cornelis F. and Bürkle, Alexander and Xu, Xingzhi and Wang, Zhao-Qi}, note={Article Number: 2993} }
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