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-Structure paper
| Title | Structural basis of PARP2 recognition of nucleosomal DNA breaks and inhibitor trapping. |
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| Journal, issue, pages | Nucleic Acids Res, Vol. 54, Issue 18, Year 2026 |
| Publish date | Sep 22, 2026 |
 Authors | Chathuni Jayathilake / Emily R Gregory-Lott / Rajbinder K Virk / Grace K Koh / Eun Cho / Tae Hun Kim /  |
| 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 ...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. |
 External links | Nucleic Acids Res / PubMed:42831429 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 1.99 - 6.63 Å |
| Structure data | EMDB-56267, PDB-9tun: EMDB-73092, PDB-9ylr:  EMDB-74590: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 1, Consensus map  EMDB-74593: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 1, Focused map  EMDB-74595: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 2, Consensus map  EMDB-74597: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 1, Consensus map  EMDB-74598: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 2, Focused map  EMDB-74600: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 1, Focus map  EMDB-74601: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 2, Consensus map  EMDB-74602: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 2, Focus map  EMDB-74603: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 3, Consensus map  EMDB-74604: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 3, Consensus map  EMDB-74605: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 3, Focus map  EMDB-74606: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 3, Focused map  EMDB-74607: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 6, Consensus map  EMDB-74609: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 4, Consensus map  EMDB-74610: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 4, Focus map  EMDB-74611: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 6, Focus map  EMDB-74612: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 7, Consensus map  EMDB-74613: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 7, Focus map  EMDB-74631: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 5, Consensus map  EMDB-74632: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 5, Focus map  EMDB-74633: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 6, Consensus map  EMDB-74634: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 6, Focus map  EMDB-74635: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 8, Consensus map  EMDB-74636: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 8, Focus map  EMDB-74637: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 9, Consensus map  EMDB-74638: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 9, Focus map  EMDB-74647: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 7, Consensus map  EMDB-74648: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 7, Focus map  EMDB-74649: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 2, Consensus map  EMDB-74651: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 3, Consensus map  EMDB-74652: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 3, Focus map  EMDB-74653: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 2, Focus map  EMDB-74659: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 4, Consensus map  EMDB-74660: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 4, Focus map  EMDB-74661: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 6, Consensus map  EMDB-74662: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 7, Consensus map  EMDB-74663: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and EB47, Class 6, Focus map  EMDB-74669: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 2, Consensus map  EMDB-74671: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 1, Consensus map  EMDB-74672: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 2, Focus map  EMDB-74673: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 3, Consensus map  EMDB-74674: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 3, Focus map  EMDB-74676: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 4, Consensus map  EMDB-74677: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 4, Focus map  EMDB-74679: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 5, Consensus map  EMDB-74682: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 5, Focus map  EMDB-74686: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 6, Consensus map  EMDB-74687: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 6, Focus map  EMDB-74689: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 1, Consensus map  EMDB-74690: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Olaparib, Class 1, Focus map EMDB-74691, PDB-9zs5: EMDB-74693, PDB-9zs6:  EMDB-74703: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 1, Consensus map  EMDB-74704: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 1, Focus map  EMDB-74705: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 2, Consensus map  EMDB-74707: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 2, Focus map  EMDB-74709: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 3, Consensus map  EMDB-74710: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 3, Focus map EMDB-74711, PDB-9zsg: EMDB-74712, PDB-9zsi: EMDB-74713, PDB-9zsj:  EMDB-74714: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 4, Consensus map  EMDB-74715: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 4, Focus map EMDB-74716, PDB-9zsk: EMDB-74717, PDB-9zsl: EMDB-74719, PDB-9zsm: EMDB-74720, PDB-9zso: EMDB-74721, PDB-9zsp:  EMDB-74722: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 5, Consensus map EMDB-74723, PDB-9zsq: EMDB-74724, PDB-9zsr: EMDB-74725, PDB-9zss: EMDB-74726, PDB-9zst: EMDB-74727, PDB-9zsu: EMDB-74728, PDB-9zsw: EMDB-74729, PDB-9zsx: EMDB-74730, PDB-9zsy: EMDB-74731, PDB-9zsz: EMDB-74745, PDB-9zta:  EMDB-74747: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 7, Consensus map  EMDB-74748: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 7, Focus map EMDB-74749, PDB-9ztd: EMDB-74750, PDB-9zte: EMDB-74751, PDB-9ztf: EMDB-74752, PDB-9ztg: EMDB-74753, PDB-9zth: EMDB-74754, PDB-9zti:  EMDB-74758: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 8, Consensus map  EMDB-74759: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 8, Focus map  EMDB-74760: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 5, Focus map  EMDB-74761: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 9, Consensus map  EMDB-74762: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 9, Focus map EMDB-74764, PDB-9ztm: EMDB-74766, PDB-9ztn: EMDB-74767, PDB-9zto: EMDB-74768, PDB-9ztp: EMDB-74769, PDB-9ztq: EMDB-74770, PDB-9ztr: EMDB-74771, PDB-9zts: EMDB-74773, PDB-9ztu: EMDB-74775, PDB-9ztw: EMDB-74776, PDB-9ztx:  EMDB-74777: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 9, Consensus map EMDB-74778, PDB-9zty:  EMDB-74780: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 10, Focus map  EMDB-74782: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 10, Consensus map  EMDB-74783: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2 and HPF1, Class 9, Focus EMDB-74784, PDB-9ztz: EMDB-74785, PDB-9zu0:  EMDB-74790: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 11, Consensus map  EMDB-74791: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 11, Focus map EMDB-74793, PDB-9zu5: EMDB-74795, PDB-9zu7: EMDB-74796, PDB-9zu8: EMDB-74800, PDB-9zua:  EMDB-74803: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, HPF1, and Talazoparib, Class 14, Consensus map  EMDB-74804: Nucleosome with an SSB at SHL +5.3 in complex with human PARP2, Class 14, Focus map EMDB-74928, PDB-9zxl: EMDB-74941, PDB-9zy2: EMDB-74947, PDB-9zyc:  EMDB-75017: Nucleosome with an SSB at SHL +5.3 in complex with the WGR domain of human PARP2, Class 1, consensus map  EMDB-75018: Nucleosome with an SSB at SHL +5.3 in complex with the WGR domain of human PARP2, Class 1, focus map  EMDB-75019: Nucleosome with an SSb at SHL +5.3 in complex with the WGR domain of PARP2, Class 2, consensus map  EMDB-75021: Nucleosome with an SSB at SHL +5.3 in complex with the WGR domain of human PARP2, Class 2, focus map EMDB-75022, PDB-9zzz: |
| Source |
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 Keywords | DNA BINDING PROTEIN / DNA damage binding protein; DNA BINDING PROTEIN / Nucleosome / Single-chain variable fragment / Nicked DNA / DNA BINDING PROTEIN/DNA / DNA damage sensing / DNA BINDING PROTEIN-DNA complex / DNA damage binding protein / DNA damage sensing protein |
drosophila melanogaster (fruit fly)
homo sapiens (human)
mus musculus (house mouse)