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

Dutta, Arijit; Hromas, Robert; Sung, Patrick

doi:10.5772/intechopen.90215

Cited by 3 publications

(3 citation statements)

References 122 publications

(136 reference statements)

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“…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].…”

Section: Alsmentioning

confidence: 99%

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

Shadfar

Parakh

Jamali

et al. 2023

Transl Neurodegener

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Redox homeostasis refers to the balance between the production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), and their elimination by antioxidants. It is linked to all important cellular activities and oxidative stress is a result of imbalance between pro-oxidants and antioxidant species. Oxidative stress perturbs many cellular activities, including processes that maintain the integrity of DNA. Nucleic acids are highly reactive and therefore particularly susceptible to damage. The DNA damage response detects and repairs these DNA lesions. Efficient DNA repair processes are therefore essential for maintaining cellular viability, but they decline considerably during aging. DNA damage and deficiencies in DNA repair are increasingly described in age-related neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease. Furthermore, oxidative stress has long been associated with these conditions. Moreover, both redox dysregulation and DNA damage increase significantly during aging, which is the biggest risk factor for neurodegenerative diseases. However, the links between redox dysfunction and DNA damage, and their joint contributions to pathophysiology in these conditions, are only just emerging. This review will discuss these associations and address the increasing evidence for redox dysregulation as an important and major source of DNA damage in neurodegenerative disorders. Understanding these connections may facilitate a better understanding of disease mechanisms, and ultimately lead to the design of better therapeutic strategies based on preventing both redox dysregulation and DNA damage.

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Section: Alsmentioning

confidence: 99%

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

Shadfar

Parakh

Jamali

et al. 2023

Transl Neurodegener

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

2022

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Meiosis is specialized cell division during gametogenesis that produces genetically unique gametes via homologous recombination. Meiotic homologous recombination entails repairing programmed 200–300 DNA double-strand breaks generated during the early prophase. To avoid interference between meiotic gene transcription and homologous recombination, mammalian meiosis is thought to employ a strategy of exclusively transcribing meiotic or post-meiotic genes before their use. Recent studies have shown that R-loops, three-stranded DNA/RNA hybrid nucleotide structures formed during transcription, play a crucial role in transcription and genome integrity. Although our knowledge about the function of R-loops during meiosis is limited, recent findings in mouse models have suggested that they play crucial roles in meiosis. Given that defective formation of an R-loop can cause abnormal transcription and transcription-coupled DNA damage, the precise regulatory network of R-loops may be essential in vivo for the faithful progression of mammalian meiosis and gametogenesis.

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Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence

Li,

Shao

2024

Antioxidants

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Oxidative stress, driven by reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), induces DNA double-strand breaks (DSBs) that compromise genomic integrity. The DNA Damage Response (DDR), primarily mediated by ATM and ATR kinases, is crucial for recognizing and repairing DSBs. Senataxin (SETX), a DNA/RNA helicase, is critical in resolving R-loops, with mutations in SETX associated with neurodegenerative diseases. This study uncovers a novel function of senataxin in modulating DDR and its impact on cellular senescence. Senataxin is shown to be crucial not only for DSB repair but also for determining cell fate under oxidative stress. SETX knockout cells show impaired DSB repair and prolonged ATM/ATR signaling detected by Western blotting, leading to increased senescence, as indicated by elevated β-galactosidase activity following H2O2 exposure and I-PpoI-induced DSBs. Wild-type cells exhibit higher apoptosis levels compared to SETX knockout cells under H2O2 treatment, suggesting that senataxin promotes apoptosis over senescence in oxidative stress. This indicates that senataxin plays a protective role against the accumulation of senescent cells, potentially mitigating age-related cellular decline and neurodegenerative disease progression. These findings highlight senataxin as a critical mediator in DDR pathways and a potential therapeutic target for conditions where cellular senescence contributes to disease pathology.

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

Cited by 3 publications

References 122 publications

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

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

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

Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence

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