title: Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration.
abstract: 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: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, UK.
authors: Matthias
authors: M
authors: Groh
authors: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, UK.
authors: Laura Oana
authors: LO
authors: Albulescu
authors: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, UK.
authors: Agnese
authors: A
authors: Cristini
authors: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, UK. Electronic address: natalia.gromak@path.ox.ac.uk.
authors: Natalia
authors: N
authors: Gromak
mesh_terms: D004265:DNA Helicases; D005786:Gene Expression Regulation; D006801:Humans; D064251:Multifunctional Enzymes; D019636:Neurodegenerative Diseases / Q000235:genetics*; D020365:RNA Helicases / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D064251:Multifunctional Enzymes; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases
keywords: R-loops; RNA/DNA hybrids; SETX; Sen1; transcription