Summary information and primary citation
- PDB-id
-
9ztq;
DSSR-derived features in text and
JSON formats
- Class
- DNA binding protein
- Method
- cryo-EM (2.63 Å)
- Summary
- Nucleosome with an ssb at shl +5.3 in complex with
human parp2, class 5
- Reference
-
Jayathilake C, Gregory-Lott ER, Virk RK, Koh GK, Cho E,
Kim TH (2026): "Structural
basis of PARP2 recognition of nucleosomal DNA breaks and
inhibitor trapping." Nucleic Acids Res.,
54. doi: 10.1093/nar/gkag939.
- 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.
