University of Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, BIOSIT - UMS3480, Rennes, France.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Nat Struct Mol Biol. 2023 May;30(5):678-691. doi: 10.1038/s41594-023-00977-x. Epub 2023 Apr 27.
Poly(ADP-ribose) polymerase 1 (PARP1) activity is regulated by its co-factor histone poly(ADP-ribosylation) factor 1 (HPF1). The complex formed by HPF1 and PARP1 catalyzes ADP-ribosylation of serine residues of proteins near DNA breaks, mainly PARP1 and histones. However, the effect of HPF1 on DNA repair regulated by PARP1 remains unclear. Here, we show that HPF1 controls prolonged histone ADP-ribosylation in the vicinity of the DNA breaks by regulating both the number and length of ADP-ribose chains. Furthermore, we demonstrate that HPF1-dependent histone ADP-ribosylation triggers the rapid unfolding of chromatin, facilitating access to DNA at sites of damage. This process promotes the assembly of both the homologous recombination and non-homologous end joining repair machineries. Altogether, our data highlight the key roles played by the PARP1/HPF1 complex in regulating ADP-ribosylation signaling as well as the conformation of damaged chromatin at early stages of the DNA damage response.
聚（ADP-核糖）聚合酶 1（PARP1）的活性受其辅因子组蛋白聚（ADP-核糖）因子 1（HPF1）的调节。由 HPF1 和 PARP1 形成的复合物催化 DNA 断裂附近蛋白质丝氨酸残基的 ADP-核糖基化，主要是 PARP1 和组蛋白。然而，HPF1 对 PARP1 调节的 DNA 修复的影响尚不清楚。在这里，我们表明 HPF1 通过调节 ADP-核糖链的数量和长度来控制 DNA 断裂附近组蛋白 ADP-核糖基化的延长。此外，我们证明 HPF1 依赖性组蛋白 ADP-核糖基化引发染色质的快速解折叠，有利于在损伤部位获得 DNA。这个过程促进了同源重组和非同源末端连接修复机制的组装。总之，我们的数据强调了 PARP1/HPF1 复合物在调节 DNA 损伤反应早期 ADP-核糖基化信号以及受损染色质构象方面的关键作用。
