期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 429, 期 21, 页码 3181-3195出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2016.10.021
关键词
SETX; RNA/DNA hybrids; R-loops; transcription; Sen1
资金
- Royal Society University Research Fellowship
- MRC NIRG [MR/J007870/1]
- John Fell Award
- Ataxia UK/Motor Neuron Diseases Association [Gromak/Jun11/6278]
- Ataxia UK [7126] Funding Source: researchfish
- Medical Research Council [MR/J007870/1] Funding Source: researchfish
- Motor Neurone Disease Association [Gromak/Jun11/6278] Funding Source: researchfish
- MRC [MR/J007870/1] Funding Source: UKRI
R-loops comprise an RNA/DNA hybrid and a displaced single-stranded DNA. They play crucial biological functions and are implicated in neurological diseases, including ataxias, amyotrophic lateral sclerosis, nucleotide expansion disorders (Friedreich ataxia and fragile X syndrome), and cancer. Currently, it is unclear which mechanisms cause R-loop structures to become pathogenic. The RNA/DNA helicase senataxin (SETX) is one of the best characterised R-loop-binding factors in vivo. Mutations in SETX are linked to two neurodegenerative disorders: ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4). SETX is known to play a role in transcription, neurogenesis, and antiviral response. Here, we review the causes of R-loop dysregulation in neurodegenerative diseases and how these structures contribute to pathomechanisms. We will discuss the importance of SETX as a genome guardian in suppressing aberrant R-loop formation and analyse how SETX mutations can lead to neurodegeneration in AOA2/ALS4. Finally, we will discuss the implications for other R-loop-associated neurodegenerative diseases and point to future therapeutic approaches to treat these disorders. (C) 2016 Elsevier Ltd. All rights reserved.
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