Senataxin, the yeast Sen1p orthologue: Characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease

Chen, Ying Zhang; Hashemi, Sayed Hossein; Anderson, Susan K.; Huang, Yongzhao; Moreira, Maria João; Lynch, David R.; Glass, Ian A.; Chance, Phillip F.; Bennett, Craig L.

doi:10.1016/j.nbd.2006.02.007

Cited by 103 publications

(100 citation statements)

References 28 publications

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“…Numerous enzymatic activities linked to the suppression of RNA:DNA hybrids including the THOcomplex (37), the mRNA polyadenylation factor Pbp1, G4-quadruplex binding proteins Stem1 and Pif1 (10,62), or the Sen1 subunit of the Nrd1 complex (20,21,63) may also be required to avoid TIR events. Mutations in the yeast Sen1 ortholog senataxin have been shown to be associated with human AOA2/ ALS4 neurodegenerative disorders (64,65). Indeed, Senataxin is needed to maintain genome integrity because of its function in the coordination of transcription, DNA replication, and the DNA damage response (reviewed in ref.…”

Section: Which Factors and Mechanism Would Participate In Transcription-mentioning

confidence: 99%

Role for RNA:DNA hybrids in origin-independent replication priming in a eukaryotic system

Stuckey

García‐Rodríguez

Aguilera

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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DNA replication initiates at defined replication origins along eukaryotic chromosomes, ensuring complete genome duplication within a single S-phase. A key feature of replication origins is their ability to control the onset of DNA synthesis mediated by DNA polymerase-α and its intrinsic RNA primase activity. Here, we describe a novel origin-independent replication process that is mediated by transcription. RNA polymerase I transcription constraints lead to persistent RNA:DNA hybrids (R-loops) that prime replication in the ribosomal DNA locus. Our results suggest that eukaryotic genomes have developed tools to prevent R-loop-mediated replication events that potentially contribute to copy number variation, particularly relevant to carcinogenesis.D uring transcription, DNA acts as a template for the synthesis of the nascent RNA. RNA synthesis is accompanied by the generation of positive and negative DNA supercoiling in front of and behind the transcription machinery, respectively (1). Unwinding of the DNA double helix by negative supercoiling may allow the RNA to hybridize to its DNA template behind the elongating RNA polymerase, leading to R-loops (2). Other elements that could potentiate R-loop accumulation include RNA: DNA hybrid-facilitating DNA sequences, such as G-quadruplex structures (3) or nicks in the nontemplate DNA strand (4).Eukaryotic cells need to control R-loop formation to avoid replication impairment, genome instability, and life span shortening mediated by such intermediates (5-10; reviewed in ref. 11). To do so, cells catalyze the relaxation of supercoiled DNA by type I topoisomerases (12-15), thus preventing replication fork reversal (16), DNA overwinding with the potential to block replication fork progression (17), DNA unwinding (18), or R-loop-mediated blocks of ribosomal RNA synthesis (19). Other enzymatic activities involved in R-loop processing include ribonuclease H (RNase H) activities, DNA-RNA helicases, such as Sen1/senataxin (20, 21), or Ataxin-2 RNA-binding protein Pbp1 (10). The ribonuclease activity of Saccharomyces cerevisiae RNases H1 and H2 specifically cleaves the RNA moiety of the RNA:DNA hybrid structure (22), whereas RNase H2 and topoisomerase 1 (Top1) can also process ribonucleotides in duplex DNA (23,24).Notably, R-loops are required to initiate mitochondrial DNA replication (25) and pioneering studies connected R-loops to origin-independent replication in prokaryotic systems (26,27). For example, DnaA-dependent initiation of DNA replication at the Escherichia coli oriC replication origin can be overcome in the absence of RNase H1 (28, 29). As a consequence, rnhA mutants can survive complete inactivation of oriC by transcriptiondependent activation of so-called oriK sites (30, 31), although candidate oriK sites have been identified only recently (32). Additional evidence for R-loop-primed replication was given by the observation that rnhA mutants are prone to an increase in mutation and DNA amplification events if origin activity is suppressed. These events required remov...

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Section: Which Factors and Mechanism Would Participate In Transcription-mentioning

confidence: 99%

Role for RNA:DNA hybrids in origin-independent replication priming in a eukaryotic system

Stuckey

García‐Rodríguez

Aguilera

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, mutations in SETX lead to two neurological disorders, an autosomal dominant form, ALS4 (amyotrophic lateral sclerosis type 4) (Blair et al 2000), and an autosomal recessive form, AOA2 (ataxiaoculomotor apraxia type 2) (Moreira et al 2004;Chen et al 2006). Although the only characterized role of SETX in humans is its involvement in DNA damage repair (Suraweera et al 2007), it will be interesting to determine whether SETX also functions in transcription termination, particularly in neurons.…”

Section: Rat1/xrn2: the Transcription Termination Torpedomentioning

confidence: 99%

Transcription termination by nuclear RNA polymerases

Richard

Manley²

2009

Genes Dev.

291

326

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Gene transcription in the cell nucleus is a complex and highly regulated process. Transcription in eukaryotes requires three distinct RNA polymerases, each of which employs its own mechanisms for initiation, elongation, and termination. Termination mechanisms vary considerably, ranging from relatively simple to exceptionally complex. In this review, we describe the present state of knowledge on how each of the three RNA polymerases terminates and how mechanisms are conserved, or vary, from yeast to human.

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“…Individuals with mutations in SETX exhibit motor neuron degeneration, together with progressive muscle weakness and atrophy. Unfortunately, at this time, little is known about the product of SETX, senataxin, except that it is a 300-kDa protein that has putative RNA/DNA helicase activity and interacts with RNA polymerase II (Pol II) (16,17). Like yeast sen1 mutants, human cell lines defective for SETX exhibit defects in transcription termination, and recent evidence supports a role in the resolution of R-loop structures that arise at transcription pause sites (17,18).…”

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confidence: 99%

Senataxin, Defective in the Neurodegenerative Disorder Ataxia with Oculomotor Apraxia 2, Lies at the Interface of Transcription and the DNA Damage Response

Yüce

West

2013

Molecular and Cellular Biology

176

161

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The neurodegenerative disorder ataxia with oculomotor apraxia 2 (AOA-2) is caused by defects in senataxin, a putative RNA/ DNA helicase thought to be involved in the termination of transcription at RNA polymerase pause sites. RNA/DNA hybrids (R loops) that arise during transcription pausing lead to genome instability unless they are resolved efficiently. We found that senataxin forms distinct nuclear foci in S/G 2 -phase human cells and that the number of these foci increases in response to impaired DNA replication or DNA damage. Senataxin colocalizes with 53BP1, a key DNA damage response protein, and with other factors involved in DNA repair. Inhibition of transcription using ␣-amanitin, or the dissolution of R loops by transient expression of RNase H1, leads to the loss of senataxin foci. These results indicate that senataxin localizes to sites of collision between components of the replisome and the transcription apparatus and that it is targeted to R loops, where it plays an important role at the interface of transcription and the DNA damage response.

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Senataxin, the yeast Sen1p orthologue: Characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease

Cited by 103 publications

References 28 publications

Role for RNA:DNA hybrids in origin-independent replication priming in a eukaryotic system

Role for RNA:DNA hybrids in origin-independent replication priming in a eukaryotic system

Transcription termination by nuclear RNA polymerases

Senataxin, Defective in the Neurodegenerative Disorder Ataxia with Oculomotor Apraxia 2, Lies at the Interface of Transcription and the DNA Damage Response

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