Poly(ADP-ribose)-dependent chromatin unfolding facilitates the association of DNA-binding proteins with DNA at sites of damage

Rebecca Smith (1) , Théo Lebeaupin (1) , Szilvia Juhász (2) , Catherine Chapuis (1) , Ostiane d'Augustin (1) , Stéphanie Dutertre (3) , Peter Burkovics (4) , Christian Biertümpfel (5) , Gyula Timinszky (2) , Sébastien Huet (1)

1 IGDR - Institut de Génétique et Développement de Rennes
2 Institute of Biochemistry and MTA SZBK "Lendület" Laboratory of Cell Cycle Regulation
3 SFR UMS CNRS 3480 - INSERM 018 - Biosit : biologie, santé, innovation technologique
4 Institute of Genetics - Laboratory of Replication and Genome Stability [Szeged, Hungary]
5 MPIB - Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry

The addition of poly(ADP-ribose) (PAR) chains along the chromatin fiber due to PARP1 activity regulates the recruitment of multiple factors to sites of DNA damage. In this manuscript, we investigated how, besides direct binding to PAR, early chromatin unfolding events controlled by PAR signaling contribute to recruitment to DNA lesions. We observed that different DNA-binding, but not histone-binding, domains accumulate at damaged chromatin in a PAR-dependent manner, and that this recruitment correlates with their affinity for DNA. Our findings indicate that this recruitment is promoted by early PAR-dependent chromatin remodeling rather than direct interaction with PAR. Moreover, recruitment is not the consequence of reduced molecular crowding at unfolded damaged chromatin but instead originates from facilitated binding to more exposed DNA. These findings are further substantiated by the observation that PAR-dependent chromatin remodeling at DNA lesions underlies increased DNAse hypersensitivity. Finally, the relevance of this new mode of PAR-dependent recruitment to DNA lesions is demonstrated by the observation that reducing the affinity for DNA of both CHD4 and HP1α, two proteins shown to be involved in the DNA-damage response, strongly impairs their recruitment to DNA lesions.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]

Rebecca Smith, Théo Lebeaupin, Szilvia Juhász, Catherine Chapuis, Ostiane d'Augustin, et al.. Poly(ADP-ribose)-dependent chromatin unfolding facilitates the association of DNA-binding proteins with DNA at sites of damage. Nucleic Acids Research, 2019, 47 (21), pp.11250-11267. ⟨10.1093/nar/gkz820⟩. ⟨hal-02304764⟩