Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation

Suraweera, Amila; Lim, Yi Chieh; Woods, Rick; Birrell, Geoff W.; Nasim, Talat; Bécherel, Olivier J.; Lavin, Martin F.

doi:10.1093/hmg/ddp278

Cited by 149 publications

(152 citation statements)

References 48 publications

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“…Analogously to S. cerevisiae Sen1, the human orthologue SETX has been proposed to play crucial roles in transcription termination and in the maintenance of genome integrity (Suraweera et al , 2009; Skourti‐Stathaki et al , 2011; Zhao et al , 2016). In line with its biological importance, mutations in SETX have been linked to two neurological disorders: ALS4 and AOA2.…”

Section: Resultsmentioning

confidence: 99%

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Sen1 has unique structural features grafted on the architecture of the Upf1‐like helicase family

et al. 2017

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The superfamily 1B (SF1B) helicase Sen1 is an essential protein that plays a key role in the termination of non‐coding transcription in yeast. Here, we identified the ~90 kDa helicase core of Saccharomyces cerevisiae Sen1 as sufficient for transcription termination in vitro and determined the corresponding structure at 1.8 Å resolution. In addition to the catalytic and auxiliary subdomains characteristic of the SF1B family, Sen1 has a distinct and evolutionarily conserved structural feature that “braces” the helicase core. Comparative structural analyses indicate that the “brace” is essential in shaping a favorable conformation for RNA binding and unwinding. We also show that subdomain 1C (the “prong”) is an essential element for 5′‐3′ unwinding and for Sen1‐mediated transcription termination in vitro. Finally, yeast Sen1 mutant proteins mimicking the disease forms of the human orthologue, senataxin, show lower capacity of RNA unwinding and impairment of transcription termination in vitro. The combined biochemical and structural data thus provide a molecular model for the specificity of Sen1 in transcription termination and more generally for the unwinding mechanism of 5′‐3′ helicases.

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Section: Resultsmentioning

confidence: 99%

“…Disease mutations cluster in the two most conserved regions of SETX, the N‐terminal domain and the helicase domain. Like its yeast orthologue, SETX has been assigned functions in transcription termination and in the control of R‐loop formation (Suraweera et al , 2009; Skourti‐Stathaki et al , 2011; Zhao et al , 2016). …”

Section: Introductionmentioning

confidence: 99%

Sen1 has unique structural features grafted on the architecture of the Upf1‐like helicase family

et al. 2017

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“…SETX is a RNA/DNA helicase that is responsible for unwinding R-loops around transcription termination sites. 131 This unwinding allows the 5 0 -to-3 0 exonuclease XRN2 to be recruited, thus terminating transcription. 132 Mutation of arginine to alanine at this residue and knockdown of SMN cause accumulation of RNAPII at termination regions of active genes across the genome (Fig.…”

Section: Smn and Transcriptional Regulationmentioning

confidence: 99%

SMN - A chaperone for nuclear RNP social occasions?

2016

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Survival Motor Neuron (SMN) protein localizes to both the nucleus and the cytoplasm. Cytoplasmic SMN is diffusely localized in large oligomeric complexes with core member proteins, called Gemins. Biochemical and cell biological studies have demonstrated that the SMN complex is required for the cytoplasmic assembly and nuclear transport of Sm-class ribonucleoproteins (RNPs). Nuclear SMN accumulates with spliceosomal small nuclear (sn)RNPs in Cajal bodies, sub-domains involved in multiple facets of snRNP maturation. Thus, the SMN complex forms stable associations with both nuclear and cytoplasmic snRNPs, and plays a critical role in their biogenesis. In this review, we focus on potential functions of the nuclear SMN complex, with particular emphasis on its role within the Cajal body.

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“…Mutations in human SETX (senataxin), the ortholog of yeast SEN1, cause two clinically distinct neurological diseases, ataxia-ocular apraxia 2 and juvenile amyotrophic lateral sclerosis (Chen et al 2004(Chen et al , 2006Moreira et al 2004;Duquette et al 2005;Suraweera et al 2007;Suraweera et al 2009). The yeast and human proteins are strikingly similar in their organization.…”

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confidence: 99%

Sen1p Performs Two Genetically Separable Functions in Transcription and Processing of U5 Small Nuclear RNA inSaccharomyces cerevisiae

et al. 2010

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The Saccharomyces cerevisiae SEN1 gene codes for a nuclear-localized superfamily I helicase. SEN1 is an ortholog of human SETX (senataxin), which has been implicated in the neurological disorders ataxiaocular apraxia type 2 and juvenile amyotrophic lateral sclerosis. Pleiotropic phenotypes conferred by sen1 mutations suggest that Sen1p affects multiple steps in gene expression. Sen1p is embedded in a proteinprotein interaction network involving direct binding to multiple partners. To test whether the interactions occur independently or in a dependent sequence, we examined interactions with the RNA polymerase II subunit Rpb1p, which is required for transcription, and Rnt1p, which is required for 39-end maturation of many noncoding RNAs. Mutations were identified that impair one of the two interactions without impairing the other interaction. The effects of the mutants on the synthesis of U5 small nuclear RNA were analyzed. Two defects were observed, one in transcription termination and one in 39-end maturation. Impairment of the Sen1p-Rpb1p interaction resulted in a termination defect. Impairment of the Sen1p-Rnt1p interaction resulted in a processing defect. The results suggest that the Sen1p-Rpb1p and Sen1p-Rnt1p interactions occur independently of each other and serve genetically separable purposes in targeting Sen1p to function in two temporally overlapping steps in gene expression.

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Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation

Cited by 149 publications

References 48 publications

Sen1 has unique structural features grafted on the architecture of the Upf1‐like helicase family

Sen1 has unique structural features grafted on the architecture of the Upf1‐like helicase family

SMN - A chaperone for nuclear RNP social occasions?

Sen1p Performs Two Genetically Separable Functions in Transcription and Processing of U5 Small Nuclear RNA inSaccharomyces cerevisiae

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