9ZU0

Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 10

Summary for 9ZU0

• Entry DOI: 10.2210/pdb9zu0/pdb
• EMDB information: 74785
• Descriptor: Histone H2A, Histone H2B, Histone H3, ... (9 entities in total)
• Functional Keywords: dna damage sensing protein, dna binding protein
• Biological source: Drosophila melanogaster (fruit flies); More
• Total number of polymer chains: 14
• Total formula weight: 318603.40

Authors

Gregory-Lott, E.,Jayathilake, C.,Virk, R.K.,Kim, T.H.,Khurana, A.,Mewhinney, C.,Yang, J.,Cho, E. (deposition date: 2025-12-23, release date: 2026-10-14)

Primary citation

Jayathilake, C.,Gregory-Lott, E.R.,Virk, R.K.,Koh, G.K.,Cho, E.,Kim, T.H.
Structural basis of PARP2 recognition of nucleosomal DNA breaks and inhibitor trapping.
Nucleic Acids Res., 54:-, 2026

PubMed Abstract: Single-strand DNA breaks are among the most frequent forms of DNA damage, yet how PARP2 recognizes these lesions within the constrained geometry of chromatin remains unclear. Here we use cryogenic electron microscopy (cryo-EM) to determine structures of PARP2 and HPF1 bound to nucleosomes containing a site-specific single-strand break (SSB) at superhelical location + 5.3. The structures reveal a multivalent binding mode in which the Trp-Gly-Arg (WGR) domain engages the break while the helical domain and HPF1 contact the opposing DNA gyre, spanning both DNA gyres of the nucleosome. This configuration explains the higher affinity of PARP2 for nucleosomal SSBs relative to free DNA. 3D classification resolves multiple PARP2-bound states with distinct WGR orientations and DNA backbone distortions, revealing structural plasticity during damage recognition. Comparative analysis shows that HPF1 constrains the conformational ensemble of PARP2 and promotes a defined catalytic domain architecture compatible with histone PARylation. PARP inhibitors (olaparib, talazoparib, EB-47) stabilize WGR-helical domain interfaces and make the ADP-ribosyltransferase-HPF1 catalytic module dynamic, consistent with reverse allosteric retention on damaged chromatin, while also promoting asymmetric nucleosomal DNA unwrapping. Together, these structures provide a chromatin-context framework for understanding PARP2 recognition of nucleosomal DNA breaks and how PARPis reshape these interactions to promote PARP retention and local chromatin remodeling.

PubMed: 42831429
DOI: 10.1093/nar/gkag939

Experimental method

ELECTRON MICROSCOPY (2.33 Å)