Abstract
Senataxin (SETX) is an RNA/DNA helicase implicated in transcription termination and the DNA damage response and is mutated in two distinct neurological disorders: AOA2 (ataxia oculomotor apraxia 2) and ALS4 (amyotrophic lateral sclerosis 4). Here we provide evidence that Rrp45, a subunit of the exosome, associates with SETX in a manner dependent on SETX sumoylation. We show that the interaction and SETX sumoylation are disrupted by SETX mutations associated with AOA2 but not ALS4. Furthermore, Rrp45 colocalizes with SETX in distinct foci upon induction of transcription-related DNA damage. Our results thus provide evidence for a SUMO-dependent interaction between SETX and the exosome, disrupted in AOA2, that targets the exosome to sites of DNA damage.
Keywords:
Senataxin; exosome; sumoylation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / metabolism
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Apraxias / genetics
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Apraxias / metabolism*
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DNA Damage
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DNA Helicases
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Exosome Multienzyme Ribonuclease Complex / metabolism
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Exosomes / metabolism*
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HeLa Cells
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Humans
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Multifunctional Enzymes
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Mutation
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RNA Helicases / genetics*
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RNA Helicases / metabolism*
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RNA-Binding Proteins / metabolism
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Small Ubiquitin-Related Modifier Proteins / metabolism*
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Sumoylation / genetics
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Two-Hybrid System Techniques
Substances
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EXOSC9 protein, human
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Multifunctional Enzymes
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RNA-Binding Proteins
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Small Ubiquitin-Related Modifier Proteins
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Exosome Multienzyme Ribonuclease Complex
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SETX protein, human
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DNA Helicases
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RNA Helicases
Supplementary concepts
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Amyotrophic Lateral Sclerosis 4, Juvenile