HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation

Marcin J. Suskiewicz, Florian Zobel, Tom E. H. Ogden, Pietro Fontana, Antonio Ariza, Ji-Chun Yang, Kang Zhu, Lily Bracken, William J. Hawthorne, Dragana Ahel, David Neuhaus and Ivan Ahel ()
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Marcin J. Suskiewicz: University of Oxford
Florian Zobel: University of Oxford
Tom E. H. Ogden: MRC Laboratory of Molecular Biology
Pietro Fontana: University of Oxford
Antonio Ariza: University of Oxford
Ji-Chun Yang: MRC Laboratory of Molecular Biology
Kang Zhu: University of Oxford
Lily Bracken: University of Oxford
William J. Hawthorne: MRC Laboratory of Molecular Biology
Dragana Ahel: University of Oxford
David Neuhaus: MRC Laboratory of Molecular Biology
Ivan Ahel: University of Oxford

Nature, 2020, vol. 579, issue 7800, 598-602

Abstract: Abstract The anti-cancer drug target poly(ADP-ribose) polymerase 1 (PARP1) and its close homologue, PARP2, are early responders to DNA damage in human cells1,2. After binding to genomic lesions, these enzymes use NAD+ to modify numerous proteins with mono- and poly(ADP-ribose) signals that are important for the subsequent decompaction of chromatin and the recruitment of repair factors3,4. These post-translational modifications are predominantly serine-linked and require the accessory factor HPF1, which is specific for the DNA damage response and switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine residues5–10. Here we report a co-structure of HPF1 bound to the catalytic domain of PARP2 that, in combination with NMR and biochemical data, reveals a composite active site formed by residues from HPF1 and PARP1 or PARP2 . The assembly of this catalytic centre is essential for the addition of ADP-ribose moieties after DNA damage in human cells. In response to DNA damage and occupancy of the NAD+-binding site, the interaction of HPF1 with PARP1 or PARP2 is enhanced by allosteric networks that operate within the PARP proteins, providing an additional level of regulation in the induction of the DNA damage response. As HPF1 forms a joint active site with PARP1 or PARP2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors.

Date: 2020
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DOI: 10.1038/s41586-020-2013-6

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