کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5533100 | 1550355 | 2017 | 15 صفحه PDF | دانلود رایگان |
- SETX is an RNA/DNA helicase involved in R-loop resolution in vivo.
- SETX plays a role in transcription, genome stability, neurogenesis, and antiviral response.
- Loss of SETX leads to DNA damage sensitivity, R-loop accumulation, and defects in gene expression.
- SETX mutations cause neurodegenerative disorders AOA2 and ALS4.
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.
Graphical Abstract171
Journal: Journal of Molecular Biology - Volume 429, Issue 21, 27 October 2017, Pages 3181-3195