6X0M

Bridging of double-strand DNA break activates PARP2/HPF1 to modify chromatin

6X0M の概要

• エントリーDOI: 10.2210/pdb6x0m/pdb
• EMDBエントリー: 21970 21971 21978 21979
• 分子名称: Histone PARylation factor 1, Poly [ADP-ribose] polymerase 2, DNA (167-MER), ... (4 entities in total)
• 機能のキーワード: dna repair, parp1, parp2, hpf1, adp-ribosylation, chromatin, histone modifications, gene regulation
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 421554.96

構造登録者

Halic, M.,Bilokapic, S. (登録日: 2020-05-16, 公開日: 2020-09-16, 最終更新日: 2024-03-06)

主引用文献

Bilokapic, S.,Suskiewicz, M.J.,Ahel, I.,Halic, M.
Bridging of DNA breaks activates PARP2-HPF1 to modify chromatin.
Nature, 585:609-613, 2020

PubMed Abstract: Breaks in DNA strands recruit the protein PARP1 and its paralogue PARP2 to modify histones and other substrates through the addition of mono- and poly(ADP-ribose) (PAR). In the DNA damage responses, this post-translational modification occurs predominantly on serine residues and requires HPF1, an accessory factor that switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine. 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. Here, to understand the molecular mechanism by which PARP enzymes recognize DNA breaks within chromatin, we determined the cryo-electron-microscopic structure of human PARP2-HPF1 bound to a nucleosome. This showed that PARP2-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 PARP2 that signal the recognition of a DNA break to the catalytic domain, which licenses HPF1 binding and PARP2 activation. Our data suggest that active PARP2 cycles through different conformational states to exchange NAD and substrate, which may enable PARP enzymes to act processively while bound to chromatin. The processes of PARP activation and the PARP catalytic cycle we describe can explain mechanisms of resistance to PARP inhibitors and will aid the development of better inhibitors as cancer treatments.

PubMed: 32939087
DOI: 10.1038/s41586-020-2725-7

実験手法

ELECTRON MICROSCOPY (6.3 Å)