PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage.
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.
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9RQ, UK and School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG.
Stuart L
SL
Rulten
Amy
A
Rotheray
Ryan L
RL
Green
Gabrielle J
GJ
Grundy
Duncan A Q
DA
Moore
Fernando
F
Gómez-Herreros
Majid
M
Hafezparast
Keith W
KW
Caldecott
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D006801:Humans; D051379:Mice; D009154:Mutation; D010084:Oxidation-Reduction; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*
D034702:RNA-Binding Protein FUS; D011064:Poly Adenosine Diphosphate Ribose; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases