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

Abstract : 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.
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Submitted on : Friday, June 28, 2019 - 9:31:07 AM
Last modification on : Tuesday, September 24, 2019 - 4:17:40 PM

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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 , Elsevier Inc, 2019, 27 (6), pp.1809-1821.e5. ⟨10.1016/j.celrep.2019.04.031⟩. ⟨hal-02167709⟩

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