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

DOI: 10.1038/s41586-020-2013-6 DOI Help

Authors: 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)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature

State: Published (Approved)
Published: February 2020
Diamond Proposal Number(s): 9306 , 18069

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. Upon binding to genomic lesions, these enzymes utilise NAD+ to modify a plethora of proteins with mono- and poly(ADP-ribose) signals that are important for subsequent chromatin decompaction and repair factor recruitment3,4. These post-translational modification events are predominantly serine-linked and require HPF1, an accessory factor that is specific for the DNA damage response and switches the amino-acid specificity of PARP1/2 from aspartate/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 both PARP1/2 and HPF1. We further show that the assembly of this new catalytic centre is essential for DNA damage-induced protein ADP-ribosylation in human cells. In response to DNA damage and NAD+ binding site occupancy, the HPF1–PARP1/2 interaction is enhanced via allosteric networks operating within PARP1/2, providing an additional level of regulation in DNA repair induction. As HPF1 forms a joint active site with PARP1/2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors.

Journal Keywords: Chemical modification; PolyADP-ribosylation

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography