Senataxin: A Putative RNA: DNA Helicase Mutated in ALS4—Emerging Mechanisms of Genome Stability in Motor Neurons

Abstract

Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, autosomal dominant childhood-or adolescent-onset motor neuron disease caused by genetic defects in senataxin (SETX), a putative RNA-DNA helicase. Studies on the yeast SETX ortholog Sen1 revealed its role in small RNA termination pathways. It has been postulated that ALS4-associated neuronal pathologies could stem from defects in RNA metabolism and altered gene expression. Importantly, SETX prevents the accumulation of R-loops, which are potentially pathogenic RNA-DNA hybrids that stem from perturbations in transcription. SETX also interacts with the tumor suppressor BRCA1 that helps promote DNA double-strand break repair by homologous recombination. As such, SETX could contribute toward the removal of harmful R-loops and DSBs in postmitotic neurons. This chapter will visit the plausible mechanistic role of SETX in R-loop removal and DNA break repair that could prevent the activation of apoptotic cell death in neurons and pathological manifestation of ALS4.

Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases

“…Importantly, the N-terminal substrate interaction and C-terminal RNA/DNA helicase domains are conserved in Sen1, implying that the same domains may perform a similar function in human senataxin. Furthermore, sentataxin has 31 cysteine residues involved in disulphide bonding via redox-regulated PDI [366]. Moreover, residue C1554, which is expected to engage in disulphide linkage with C1509, is mutated in a sporadic case of ALS4 [367].…”

R-Loop Formation in Meiosis: Roles in Meiotic Transcription-Associated DNA Damage

“…While DNA–RNA hybrids are physiologically formed in certain regions with a physiological function, R-loops are generally considered pathological and detrimental products that interfere with the transcription process and subsequently contribute to genome instability because unstructured single-stranded DNA is targeted for damage [ 5 ]. Among the enzymes involved in R-loop biogenesis, senataxin (SETX) is an R-loop-specific DNA/RNA helicase whose C-terminal SEN1 domain shares a high similarity with yeast Sen1p [ 6 , 7 , 8 ]. Because Sen1p unwinds the R-loop [ 9 , 10 , 11 ], the probable mammalian ortholog SETX is believed to have a similar protein function; however, such activity has not yet been reported in vitro.…”

“…However, Setx deficiency does cause the accumulation of DNA damage in somatic cell lines [ 12 ]. Notably, SETX is ubiquitously expressed in various cell types, and genetic mutations of it are found in patients with amyotrophic lateral sclerosis 4 (ALS4) [ 7 , 13 ] and ataxia-oculomotor apraxia (AOA2) [ 14 , 15 ]. However, the phenotype of knockout mice is restricted to male infertility due to meiotic arrest [ 16 , 17 ], suggesting that male meiosis is the most susceptible to the effects of R-loop abnormalities in vivo.…”