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Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins

Nature volume 451, pages 81–85 (2008)Cite this article

Abstract

Post-translational modification (PTM) of proteins plays an important part in mediating protein interactions and/or the recruitment of specific protein targets1,2. PTM can be mediated by the addition of functional groups (for example, acetylation or phosphorylation), peptides (for example, ubiquitylation or sumoylation), or nucleotides (for example, poly(ADP-ribosyl)ation). Poly(ADP-ribosyl)ation often involves the addition of long chains of ADP-ribose units, linked by glycosidic ribose–ribose bonds3, and is critical for a wide range of processes, including DNA repair, regulation of chromosome structure, transcriptional regulation, mitosis and apoptosis4. Here we identify a novel poly(ADP-ribose)-binding zinc finger (PBZ) motif in a number of eukaryotic proteins involved in the DNA damage response and checkpoint regulation. The PBZ motif is also required for post-translational poly(ADP-ribosyl)ation. We demonstrate interaction of poly(ADP-ribose) with this motif in two representative human proteins, APLF (aprataxin PNK-like factor) and CHFR (checkpoint protein with FHA and RING domains), and show that the actions of CHFR in the antephase checkpoint are abrogated by mutations in PBZ or by inhibition of poly(ADP-ribose) synthesis.

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Figure 1: PAR binding/modification mediated by the PBZ zinc finger motif.
Figure 2: Interactions of APLF and CHFR with PAR are mediated by the PBZ motif.
Figure 3: Checkpoint functions, but not ubiquitylation, of CHFR are affected by PBZ mutations.

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Acknowledgements

We thank T. Lindahl (LRI, CRUK) for XRCC1, G. Smith for the PARP inhibitor KU-0058948, and J. Gannon for assistance with the Biacore. This work was supported by Cancer Research UK, the EU DNA Repair Consortium and the Louis-Jeantet Foundation. I.A. and D.A. are supported by EMBO fellowships.

Author Contributions I.A. and D.A. discovered the PBZ motif and performed most of the experiments. A.J.C. carried out supporting analyses. T.M. and J.P. defined the role of PBZ in the antephase checkpoint. S.J.B. and S.C.W. are joint senior authors who managed the project and helped write the manuscript.

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Author notes

  1. Ivan Ahel and Dragana Ahel: These authors contributed equally to this work.

Authors and Affiliations

  1. Genetic Recombination and,,

    Ivan Ahel & Stephen C. West

  2. DNA Damage Response Laboratories, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK ,

    Dragana Ahel, Allison J. Clark & Simon J. Boulton

  3. Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QR, UK ,

    Takahiro Matsusaka & Jonathon Pines

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  1. Ivan Ahel
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Corresponding authors

Correspondence to Simon J. Boulton or Stephen C. West.

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Ahel, I., Ahel, D., Matsusaka, T. et al. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature 451, 81–85 (2008). https://doi.org/10.1038/nature06420

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