HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage

Smith, Rebecca and Zentout, Siham and Rother, Magdalena and Bigot, Nicolas and Chapuis, Catherine and Mihut, Alexandra and Zobel, Florian Franz and Ahel, Ivan and van Attikum, Haico and Timinszky, Gyula and Huet, Sébastien (2023) HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 30. pp. 678-691. ISSN 1545-9993

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Abstract

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.Smith, Zentout et al. investigate the role of HPF1 in DNA repair using live-cell imaging methods and find that HPF1-dependent histone ADP-ribosylation drives early process in DNA repair, including chromatin relaxation and repair factor recruitment.

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