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. 2023 Oct 31;42(10):113199.
doi: 10.1016/j.celrep.2023.113199. Epub 2023 Oct 5.

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

Evgeniya M Mamontova  1 , Marie-Jeanne Clément  2 , Maria V Sukhanova  3 , Vandana Joshi  2 , Ahmed Bouhss  2 , Juan Carlos Rengifo-Gonzalez  2 , Bénédicte Desforges  2 , Loic Hamon  2 , Olga I Lavrik  4 , David Pastré  5
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Free article

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

Evgeniya M Mamontova et al. Cell Rep. .
Free article

Abstract

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.

Keywords: ALS; CP: Molecular biology; DNA damage response; DNA repair; FUS/TLS; RNA; RNA-binding proteins; cancer; liquid-liquid phase separation; poly(ADP-ribose); poly(ADP-ribose) polymerase 1.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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