PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage

Rulten, Stuart L, Rotheray, Amy, Green, Ryan L, Grundy, Gabrielle J, Moore, Duncan A Q, Gómez-Herreros, Fernando, Hafezparast, Majid and Caldecott, Keith W (2014) PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage. Nucleic Acids Research, 42 (1). pp. 307-314. ISSN 1362-4962

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Abstract

Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUS(R521G), harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: Q Science > Q Science (General)
Depositing User: Majid Hafezparast
Date Deposited: 14 Nov 2013 12:57
Last Modified: 06 Mar 2017 01:19
URI: http://sro.sussex.ac.uk/id/eprint/47026

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Project NameSussex Project NumberFunderFunder Ref
Amyotrophic Lateral Sclerosis and the DNA Damage ResponseG1108MRC-MEDICAL RESEARCH COUNCILMR/K01854X/1
Chromosomal Single-strand break Repair: Mechanisms & Degenerative DiseaseG0830MRC-MEDICAL RESEARCH COUNCILMR/J006750/1