FUS RRM regulates poly(ADP-ribose) levels after transcriptional arrest and PARP-1 activation on DNA damage

Evgeniya Mamontova (1, 2) , Marie-Jeanne Clément (1) , Maria Sukhanova (2) , Vandana Joshi (1) , Ahmed Bouhss (1) , Juan-Carlos Rengifo-Gonzalez (1) , Bénédicte Desforges (1) , Loic Hamon (1) , Olga Lavrik (2) , David Pastré (1)

1 SABNP - Structure et activité des biomolécules normales et pathologiques
2 ICBFM SB RAS - Institute of Chemical Biology and Fundamental Medicine [Novosibirsk, Russia]

PARP-1 activation at DNA damage sites leads to the synthesis of long poly(ADP-ribose) (PAR) chains, which serve as a signal for DNA repair. Here we show that FUS, an RNA-binding protein, is specifically directed to PAR through its RNA recognition motif (RRM) to increase PAR synthesis by PARP-1 in HeLa cells after genotoxic stress. Using a structural approach, we also identify specific residues located in the FUS RRM, which can be PARylated by PARP-1 to control the level of PAR synthesis. Based on the results of this work, we propose a model in which, following a transcriptional arrest that releases FUS from nascent mRNA, FUS can be recruited by PARP-1 activated by DNA damage to stimulate PAR synthesis. We anticipate that this model offers new perspectives to understand the role of FET proteins in cancers and in certain neurodegenerative diseases such as amyotrophic lateral sclerosis.

Domaines: Sciences du Vivant [q-bio]

Evgeniya Mamontova, Marie-Jeanne Clément, Maria Sukhanova, Vandana Joshi, Ahmed Bouhss, et al.. FUS RRM regulates poly(ADP-ribose) levels after transcriptional arrest and PARP-1 activation on DNA damage. Cell Reports, 2023, 42 (10), pp.113199. ⟨10.1016/j.celrep.2023.113199⟩. ⟨hal-04231448⟩