Nucl._Acids_Res.-2013-Rulten-nar_gkt835.pdf (7.03 MB)
PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage
journal contribution
posted on 2023-06-08, 16:19 authored by Stuart L Rulten, Amy Rotheray, Ryan L Green, Gabrielle J Grundy, Duncan MooreDuncan Moore, Fernando Gómez-Herreros, Majid HafezparastMajid Hafezparast, Keith CaldecottKeith CaldecottAmyotrophic 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.
Funding
Amyotrophic Lateral Sclerosis and the DNA Damage Response; G1108; MRC-MEDICAL RESEARCH COUNCIL; MR/K01854X/1
Chromosomal Single-strand break Repair: Mechanisms & Degenerative Disease; G0830; MRC-MEDICAL RESEARCH COUNCIL; MR/J006750/1
History
Publication status
- Published
File Version
- Published version
Journal
Nucleic Acids ResearchISSN
1362-4962Publisher
Oxford University PressExternal DOI
Issue
1Volume
42Page range
307-314Department affiliated with
- Neuroscience Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2013-11-14First Open Access (FOA) Date
2014-06-30First Compliant Deposit (FCD) Date
2014-06-30Usage metrics
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