PDF(Pubmed)
Abstract：
Senataxin is an RNA:DNA helicase that plays an important role in the resolution of RNA:DNA hybrids (R-loops) formed during transcription. R-loops are involved in the regulation of biological processes such as immunoglobulin class switching, gene expression and DNA repair. Excessive accumulation of R-loops results in DNA damage and loss of genomic integrity. Senataxin is critical for maintaining optimal levels of R-loops to prevent DNA damage and acts as a genome guardian. Within the nucleus, senataxin interacts with various RNA processing factors and DNA damage response and repair proteins. Senataxin interactors include survival motor neuron and zinc finger protein 1, with whom it co-localizes in sub-nuclear bodies. Despite its ubiquitous expression, mutations in senataxin specifically affect neurons and result in distinct neurodegenerative diseases such as amyotrophic lateral sclerosis type 4 and ataxia with oculomotor apraxia type 2, which are attributed to the gain-of-function and the loss-of-function mutations in senataxin, respectively. In addition, low levels of senataxin (loss-of-function) in spinal muscular atrophy result in the accumulation of R-loops causing DNA damage and motor neuron degeneration. Senataxin may play multiple functions in diverse cellular processes; however, its emerging role in R-loop resolution and maintenance of genomic integrity is gaining attention in the field of neurodegenerative diseases. In this review, we highlight the role of senataxin in R-loop resolution and its potential as a therapeutic target to treat neurodegenerative diseases.
摘要：
Senataxin是一种RNA：DNA解旋酶，在转录过程中形成的RNA：DNA杂交体（R环）的解析中起着重要作用。R环参与生物过程的调节，如免疫球蛋白类别转换，基因表达和DNA修复。R环的过度积累导致DNA损伤和基因组完整性的丧失。Senataxin对于维持R环的最佳水平以防止DNA损伤至关重要，并充当基因组监护人。在细胞核内，Senataxin与各种RNA加工因子和DNA损伤反应和修复蛋白相互作用。Senataxin相互作用者包括存活运动神经元和锌指蛋白1，与它们共同定位在亚核体内。尽管它无处不在，senataxin中的突变特异性影响神经元并导致不同的神经退行性疾病，如4型肌萎缩侧索硬化症和2型动眼失用症的共济失调，这归因于senataxin中的功能获得和功能丧失突变，分别。此外,脊髓性肌萎缩症中低水平的senataxin（功能丧失）导致R-loop的积累，引起DNA损伤和运动神经元变性。Senataxin可能在不同的细胞过程中发挥多种功能;然而，其在R-loop分辨率和维持基因组完整性方面的新兴作用正在神经退行性疾病领域获得关注。在这次审查中,我们强调了senataxin在R-loop分辨率中的作用及其作为治疗神经退行性疾病的治疗靶点的潜力.
