Fused in Sarcoma (FUS) in DNA Repair: Tango with Poly(ADP-ribose) Polymerase 1 and Compartmentalisation of Damaged DNA.

Maria V Sukhanova,David Pastré,Olga I Lavrik,Anastasia S Singatulina

doi:10.3390/ijms21197020

Abstract

The fused in sarcoma (FUS) protein combines prion-like properties with a multifunctional DNA/RNA-binding domain and has functions spanning the regulation of RNA metabolism, including transcription, pre-mRNA splicing, mRNA transport and translation. In addition to its roles in RNA metabolism, FUS is implicated in the maintenance of DNA integrity. In this review, we examine the participation of FUS in major DNA repair pathways, focusing on DNA repair associated with poly(ADP-ribosyl)ation events and on how the interaction of FUS with poly(ADP-ribose) may orchestrate transient compartmentalisation of DNA strand breaks. Unravelling how prion-like RNA-binding proteins control DNA repair pathways will deepen our understanding of the pathogenesis of some neurological diseases and cancer as well as provide the basis for the development of relevant innovative therapeutic technologies. This knowledge may also extend the range of applications of poly(ADP-ribose) polymerase inhibitors to the treatment of neurodegenerative diseases related to RNA-binding proteins in the cell, e.g., amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

Highlights

Throughout their lifespan organisms are constantly exposed to genotoxic agents, both exogenous and endogenous
The maintenance of genome stability is achieved by the machineries associated with the DNA damage response (DDR) and the cell death pathways that carry out detection of DNA damage or a signal of its presence to orchestrate DNA repair and induce cell death upon massive DNA damage, respectively [5,6]
The interaction of RNA-binding proteins (RBPs) with the PAR produced in response to DNA damage is currently receiving increasing attention because PAR contributes to the recruitment of RBPs to a DNA repair site and promotes their LLPS

Summary

Introduction

Throughout their lifespan organisms are constantly exposed to genotoxic agents, both exogenous and endogenous. A rough assessment has revealed that up to 70,000 DNA damage events occur per human cell per day [1] Under these conditions, preserving cell genome integrity is one of the most important challenges faced by multicellular organisms. More and more studies are revealing the direct functions of many RBPs in the presence of DNA damage, e.g., sensing, signalling, and repair [11,12,13]. In addition to its role in RNA metabolism, FUS was recently implicated in the maintenance of DNA integrity in response to DNA damage [33,34]. We highlight the role of FUS in the maintenance of genome integrity, focusing on PARylation events and on how the FUS–PAR interaction may be connected with DNA repair

Intrinsically Disordered Regions and Prion-Like Properties of FUS

Deficiency of FUS or Mutations of FUS Affect the Repair of DNA Strand Breaks

FUS Is Connected to DNA Strand Breaks by PARPs’ Signalling Activities

DNA Damage Sensing by the Phase Separation of FUS?

Conclusions