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. 2023 May;30(5):678-691.
doi: 10.1038/s41594-023-00977-x. Epub 2023 Apr 27.

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

Rebecca Smith #  1   2 , Siham Zentout #  3 , Magdalena Rother  4 , Nicolas Bigot  3 , Catherine Chapuis  3 , Alexandra Mihuț  5   6 , Florian Franz Zobel  7 , Ivan Ahel  7 , Haico van Attikum  4 , Gyula Timinszky  8 , Sébastien Huet  9   10
Affiliations

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

Rebecca Smith et al. Nat Struct Mol Biol. 2023 May.

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.

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