Bridging of DNA breaks activates PARP2-HPF1 to modify chromatin.

Breaks in DNA strands recruit the protein and its paralogue to modify histones and other substrates through the addition of mono- and poly(ADP-ribose) (PAR)^1-5. In the DNA damage responses, this post-translational modification occurs predominantly on serine residues^6-8 and requires HPF1, an accessory factor that switches the amino acid specificity of Pduanyu371 and Pduanyu372 from aspartate or glutamate to serine^9,10. Poly(ADP) ribosylation (PARylation) is important for subsequent chromatin decompaction and provides an anchor for the recruitment of downstream signalling and repair factors to the sites of DNA breaks^2,11. Here, to understand the molecular mechanism by which enzymes recognize DNA breaks within chromatin, we determined the cryo-electron-microscopic structure of human bound to a nucleosome. This showed that Pduanyu372-HPF1 bridges two nucleosomes, with the broken DNA aligned in a position suitable for ligation, revealing the initial step in the repair of double-strand DNA breaks. The bridging induces structural changes in Pduanyu372 that signal the recognition of a DNA break to the catalytic domain, which licenses HPF1 binding and Pduanyu372 activation. Our data suggest that active Pduanyu372 cycles through different conformational states to exchange NAD⁺ and substrate, which may enable Pduanyu37 enzymes to act processively while bound to chromatin. The processes of Pduanyu37 activation and the Pduanyu37 catalytic cycle we describe can explain mechanisms of resistance to Pduanyu37 inhibitors and will aid the development of better inhibitors as cancer treatments^12-16.

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