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TitlePARP1-HPF1 structure and dynamics on nicked DNA suggest a mechanism for acute and localized ADP-ribosylation.
Journal, issue, pagesNat Commun, Year 2026
Publish dateFeb 16, 2026
AuthorsAleksandr Sverzhinsky / Huijun Xue / Marie-France Langelier / Marcelo V Muniz Corrêa / Joshua Del Mundo / Scott Classen / Michal Hammel / Eli Rothenberg / John M Pascal /
PubMed AbstractPARP1 detection of DNA strand breaks allosterically leads to PARP1 synthesis of poly(ADP-ribose) modifications that signal DNA damage. HPF1 engages activated PARP1 to control modification site ...PARP1 detection of DNA strand breaks allosterically leads to PARP1 synthesis of poly(ADP-ribose) modifications that signal DNA damage. HPF1 engages activated PARP1 to control modification site selection. Understanding of the mechanism of DNA break detection and catalytic activation is incomplete, due largely to limited structural information for full-length PARP1. Here, single-particle cryo-EM provides views of the full complement of PARP1 domains engaging a DNA single-strand break in the presence of HPF1 and a fragment of binding partner Timeless. Cryo-EM, single-molecule DNA dynamics, and small-angle X-ray scattering analysis indicate that PARP1 remains dynamic even when the multi-domain structure is organized on a DNA break, with the minimal catalytic region displaying high mobility relative to domains engaging damage. We propose that the organization of PARP1 domains on a DNA break releases a tethered, constitutively active catalytic region to modify molecules in a radius surrounding the DNA break site.
External linksNat Commun / PubMed:41698892
MethodsEM (single particle)
Resolution3.6 - 4.3 Å
Structure data

48285

9mi8

EMDB-48285, PDB-9mi8:
Human PARP1 N-terminal domains bound to nicked DNA
Method: EM (single particle) / Resolution: 3.6 Å

48313

9mja

EMDB-48313, PDB-9mja:
PARP1 ART in complex with HPF1 and EB47
Method: EM (single particle) / Resolution: 4.3 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-UHB:
2-[4-[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]carbonylpiperazin-1-yl]-N-(1-oxidanylidene-2,3-dihydroisoindol-4-yl)ethanamide

Source
  • homo sapiens (human)
KeywordsDNA BINDING PROTEIN / PARP1 / Zinc-finger domains / nicked DNA

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