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

Nature volume 579, pages 598–602 (2020)Cite this article

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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 residues5,6,7,8,9,10. 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.

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Fig. 1: HPF1 structure and regulation of the HPF1–PARP1 interaction.
Fig. 2: Crystal and solution structural analysis of the HPF1–PARP1/2 interaction.
Fig. 3: DNA damage-induced ADP-ribosylation depends on functional HPF1.
Fig. 4: HPF1-interacting PARP1/2 residues and model of DNA damage-induced ADP-ribosylation.

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Data availability

Crystallography atomic coordinates and structure factors were deposition in the Protein Data Bank (PDB) with accession codes 6TVH, 6TX1, 6TX2 and 6TX3. All other data are included in the paper and any further information will be provided upon reasonable request.

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Acknowledgements

We thank J. Rack and J. Ahel for comments on the manuscript; E. Bartlett, A. Saukko-Paavola, R. Hughes and V. Zorzini for help with biochemical experiments; E. Lowe and M. Schuller for help with X-ray diffraction data collection; T. Clausen and A. Vogel for discussions; and J. M. Pascal for sharing reagents. We thank the Diamond Light Source for access to and assistance at beamlines I03, I04, I04-1 and I24 throughout the project (proposal numbers mx9306 mx18069); the Francis Crick Institute for access to the MRC Biomedical NMR Centre, and assistance from G. Kelly (the Francis Crick Institute receives core funding from Cancer Research UK (FC001029), the UK Medical Research Council (FC001029) and the Wellcome Trust (FC001029)). Work in I.A.’s group is funded by the Wellcome Trust (grant numbers 101794 and 210634), BBSRC (BB/R007195/1) and Cancer Research UK (C35050/A22284). Work in D.N.’s group is supported by the Medical Research Council (grant U105178934). Work in D.A.’s group is funded by the Cancer Research UK Career Development Fellowship (grant number 16304). M.J.S. is supported by an EMBO Long-Term Fellowship (ALTF 879-2017). T.E.H.O. and W.J.H. are supported by an LMB/AstraZeneca BlueSkies postdoctoral fellowship (BSF22).

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Authors and Affiliations

  1. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    Marcin J. Suskiewicz, Florian Zobel, Pietro Fontana, Antonio Ariza, Kang Zhu, Lily Bracken, Dragana Ahel & Ivan Ahel

  2. MRC Laboratory of Molecular Biology, Cambridge, UK

    Tom E. H. Ogden, Ji-Chun Yang, William J. Hawthorne & David Neuhaus

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  1. Marcin J. Suskiewicz
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Contributions

I.A. conceived the project with input from M.J.S., D.N. and D.A. P.F. and A.A. solved the N. vectensis HPF1 structure. L.B. and M.J.S. solved the H. sapiens HPF1 structure. M.J.S. solved the HPF1–PARP2 structure and conducted biochemical experiments with the assistance of L.B. and K.Z. F.Z. conducted in vivo experiments. D.N., T.E.H.O., J.-C.Y. and W.J.H. conducted NMR analysis. M.J.S., I.A. and D.N. wrote the manuscript with the assistance of all authors.

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Correspondence to Ivan Ahel.

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Peer review information Nature thanks Sebastian Guettler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Structures of HPF1 from N. vectensis and H. sapiens.

Ribbon diagrams of HPF1 structures coloured according to domain organization. All three structures are shown in corresponding orientations based on a structural alignment. For N. vectensis HPF1, which crystallized with two molecules in the asymmetric unit, both molecules are shown.

Extended Data Fig. 2 Analytical SEC analysis of HPF1–PARP1 interaction.

Uncropped SDS–PAGE gels with fractions from analytical SEC. HPF1 was analysed in the presence or absence of PARP1 and either alone or with a short DNA duplex and/or the NAD+ analogue EB-47. Areas marked by grey rectangles are shown in Fig. 1d. Note the altered elution profile of PARP1 in the presence of DNA and EB-47, especially the shift in the peak centre after the addition of DNA, possibly reflecting PARP1 oligomerization.

Extended Data Fig. 3 Analytical SEC of the HPF1–PARP1(CAT) interaction.

a, Uncropped gels with fractions from analytical SEC shown in Fig. 1e. b, Analytical SEC analysis of PARP1(CAT) binding to HPF1. PARP1(CAT) was used with its lipoyl tag (Methods) uncleaved to allow it to be distinguished from HPF1, which has approximately the same molecular mass and elution profile as PARP1(CAT) (data not shown). For uncropped gels, see the HPF1 gel in a and two gels in c. c, Uncropped gels for the analysis shown in b. Contaminants of HPF1 are marked by an asterisk.

Extended Data Fig. 4 Structure of the HPF1–PARP2(CATΔHD) complex.

a, Ribbon diagrams and surface representations of the HPF1–PARP2(CATΔHD) complex. The bound NAD+ analogue, EB-47, is shown as sticks. b, Structural diagrams of the HPF1–PARP2 active site with the catalytic residues Glu284 (HPF1) and Glu545 (PARP2, equivalent to Glu988 in PARP1) and bound/modelled ligands shown as sticks, and feature-enhanced modified σ-weighted 2Fo − Fc electron density map contoured at 1σ. Left, the original EB-47-bound structure. Right, the same view with NAD+ modelled in place of EB-47 by alignment with PDB accession 6BHV (electron density belongs to EB-47). The Glu284 side-chain carboxylate group of HPF1 is located 4.5–6 Å away from the C1″ of the modelled NAD+. A tentative location of a serine substrate between NAD+ and Glu284 is indicated.

Extended Data Fig. 5 Backbone amide signal intensity ratios for PARP1(CAT) with or without HPF1.

Expansions of the histograms shown in Fig. 2d, showing backbone amide signal intensity ratios derived from [15N,1H]-TROSY spectra of 15N-labelled PARP1(CAT) measured with or without HPF1 (top) and steady-state {1H}15N NOE values for free 15N-labelled PARP1(CAT) (bottom), plotted as a function of PARP1 amino acid sequence for the HD subdomain (left) and the ART subdomain (the CAT domain without the HD) (right). Error estimates (in red) were calculated for the intensity ratios by taking the root mean squared noise intensity in each spectrum as the measurement error, with the error in intensity ratios propagated according to the standard formula σA/B = (A/B)[(σA/A)2 + (σB/B)2]1/2. For the NOE data, error estimates were calculated as described previously52.

Extended Data Fig. 6 Backbone amide NH signal assignments for PARP1(CAT).

a, [15N,1H]-TROSY spectrum of 15N-labelled human PARP1(CAT) recorded at 800 MHz and 25 °C, showing backbone amide NH signal assignments. Protein concentration was 400 μM in 50 mM [2H11]Tris, pH 7.0, 50 mM NaCl and 2 mM [2H10]DTT in 95:5 H2O/2H2O. b, Expansion of the most crowded region of the spectrum shown in a.

Extended Data Fig. 7 [15N,1H]-TROSY spectra of PARP1(CAT) with or without HPF1.

[15N,1H]-TROSY spectra of human PARP1(CAT) in the absence (grey) or presence (blue) of human full-length HPF1 at a 1:1 ratio, recorded at 800 MHz and 25 °C. Protein concentrations were 150 μM, samples contained 50 mM [2H11]Tris, pH 7.0, 50 mM NaCl and 2 mM [2H10]DTT in 95:5 H2O/2H2O. The spectra were acquired, processed and contoured identically.

Extended Data Fig. 8 Model of the HPF1–PARP1(CAT) interaction.

a, b, Additional views of the model of the HPF1–PARP1(CAT) interaction shown in Fig. 2e. The complex is shown in the same orientations with PARP1 in surface (a) and ribbon (b) representation. Colouring of PARP1(CAT) is as in the scale defined in Fig. 2e. HPF1 is coloured beige (‘wheat’) and shown in semi-transparent ribbon representation.

Extended Data Fig. 9 Structure of the HPF1–PARP2(CATΔHD) complex with modelled HD subdomain.

a, b, Ribbon diagrams of the HPF1–PARP2(CATΔHD) complex with the PARP2 HD modelled in based on a structural alignment between the PARP2(CATΔHD) fragment and a previous PARP2(CAT) structure that includes the HD (PDB code 4ZZX). Glu284 and EB-47 are shown in stick representation for orientation. The HD is shown in ribbon representation (a) and as a semi-transparent space-filling model (b). In b, examples of prominent side chains that might clash with HPF1 if this HD positioning were maintained are labelled and shown in stick representation.

Extended Data Table 1 Data collection and refinement statistics for crystal structures described in the study
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Suskiewicz, M.J., Zobel, F., Ogden, T.E.H. et al. HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation. Nature 579, 598–602 (2020). https://doi.org/10.1038/s41586-020-2013-6

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