PARP-1 Activation Directs FUS to DNA Damage Sites to Form PARG-Reversible Compartments Enriched in Damaged DNA

Anastasia Singatulina (1, 2) , Loic Hamon (1) , Maria Sukhanova (2) , Bénédicte Desforges (1) , Vandana Joshi (1) , Ahmed Bouhss (1) , Olga Lavrik (2, 3) , David Pastre (1)

1 SABNP - Structure et activité des biomolécules normales et pathologiques
2 Novosibirsk Institute of Chemical Biology and Fundamental Medecine
3 NSU - Novosibirsk State University

PARP-1 synthesizes long poly(ADP-ribose) chains(PAR) at DNA damage sites to recruit DNA repair fac-tors. Among proteins relocated on damaged DNA,the RNA-binding protein FUS is one of the mostabundant, raising the issue about its involvement inDNA repair. Here, we reconstituted the PARP-1/PAR/DNA systemin vitroand analyzed at the sin-gle-molecule level the role of FUS. We demonstratesuccessively the dissociation of FUS from mRNA,its recruitment at DNA damage sites through its bind-ing to PAR, and the assembly of damaged DNA-richcompartments. PARG, an enzyme family that hydro-lyzes PAR, is sufficient to dissociate damaged DNA-rich compartmentsin vitroand initiates the nucleocy-toplasmic shuttling of FUS in cells. We anticipatethat, consistent with previous models, FUS facilitatesDNA repair through the transient compartmentaliza-tion of DNA damage sites. The nucleocytoplasmicshuttling of FUS after the PARG-mediated compart-ment dissociation may participate in the formationof cytoplasmic FUS aggregates.

Mots clés: poly(ADP-ribose) polymerase 1; poly(ADP-ribose); RNA-binding proteins; Liquid-liquid phase separation; DNA repair; Atomic force microscopy; cancer; Neurodegenerative disease

Domaines: Sciences du Vivant [q-bio]

Anastasia Singatulina, Loic Hamon, Maria Sukhanova, Bénédicte Desforges, Vandana Joshi, et al.. PARP-1 Activation Directs FUS to DNA Damage Sites to Form PARG-Reversible Compartments Enriched in Damaged DNA. Cell Reports, 2019, 27 (6), pp.1809-1821. ⟨10.1016/j.celrep.2019.04.031⟩. ⟨hal-02167709⟩