Senataxin: genome guardian at the interface of transcription and neurodegeneration

Journal article

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.

Authors: Groh, M; Albulescu, L; Cristini, A; Gromak, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Journal of Molecular Biology
• Volume: 429
• Issue: 21
• Pages: 3181-3195
• Publication date: 2016-10-19
• Acceptance date: 2016-10-15
• DOI: 10.1016/j.jmb.2016.10.021
• EISSN: 1089-8638
• ISSN: 0022-2836
• Pmid: 27771483
• Language: English
• Keywords: neurodegenerative diseases; humans; gene expression regulation; transcription, genetic; RNA helicases