Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage

Roda, Ricardo H.; Rinaldi, Carlo; Singh, Rajat; Schindler, Alice B.; Blackstone, Craig

doi:10.1016/j.jocn.2013.11.048

Cited by 15 publications

(8 citation statements)

References 29 publications

(30 reference statements)

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“…Another published study reported a role for the SPG48 protein KIAA0415 in DNA repair . Since KIAA0415 coprecipitates with spastizin and spatacsin, we investigated the induction of, and recovery from, DNA damage induced in fibroblasts with H 2 O 2 , using an alkaline comet assay . We observed no differences among the cell lines, indicating that spastazin is dispensable for DNA repair (Fig.…”

Section: Resultsmentioning

confidence: 88%

Lysosomal abnormalities in hereditary spastic paraplegia types SPG 15 and SPG 11

Renvoisé

Chang

Singh

et al. 2014

Ann Clin Transl Neurol

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101

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ObjectiveHereditary spastic paraplegias (HSPs) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified (SPG1-71) to date. SPG15 and SPG11 are clinically similar, autosomal recessive disorders characterized by progressive spastic paraplegia along with thin corpus callosum, white matter abnormalities, cognitive impairment, and ophthalmologic abnormalities. Furthermore, both have been linked to early-onset parkinsonism.MethodsWe describe two new cases of SPG15 and investigate cellular changes in SPG15 and SPG11 patient-derived fibroblasts, seeking to identify shared pathogenic themes. Cells were evaluated for any abnormalities in cell division, DNA repair, endoplasmic reticulum, endosomes, and lysosomes.ResultsFibroblasts prepared from patients with SPG15 have selective enlargement of LAMP1-positive structures, and they consistently exhibited abnormal lysosomal storage by electron microscopy. A similar enlargement of LAMP1-positive structures was also observed in cells from multiple SPG11 patients, though prominent abnormal lysosomal storage was not evident. The stabilities of the SPG15 protein spastizin/ZFYVE26 and the SPG11 protein spatacsin were interdependent.InterpretationEmerging studies implicating these two proteins in interactions with the late endosomal/lysosomal adaptor protein complex AP-5 are consistent with shared abnormalities in lysosomes, supporting a converging mechanism for these two disorders. Recent work with Zfyve26−/− mice revealed a similar phenotype to human SPG15, and cells in these mice had endolysosomal abnormalities. SPG15 and SPG11 are particularly notable among HSPs because they can also present with juvenile parkinsonism, and this lysosomal trafficking or storage defect may be relevant for other forms of parkinsonism associated with lysosomal dysfunction.

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Section: Resultsmentioning

confidence: 88%

Lysosomal abnormalities in hereditary spastic paraplegia types SPG 15 and SPG 11

Renvoisé

Chang

Singh

et al. 2014

Ann Clin Transl Neurol

Self Cite

101

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“…Moreover, SETX mutant mice display defective meiosis and Spo11-mediated DSB persistence 20 . Finally, depletion of senataxin/Sen1p triggers sensitivity to some DNA damaging agents such as H 2 O 2 and UV 21 – 23 , a feature also observed in AOA2 patient cell lines 22 , 24 , 25 . However, senataxin depleted cells are not radiation sensitive 22 , suggesting that it may not function at sites of DNA double-strand break (DSB), a form of DNA damage largely induced upon irradiation.…”

Section: Introductionmentioning

confidence: 72%

Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations

et al. 2018

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Ataxia with oculomotor apraxia 2 (AOA-2) and amyotrophic lateral sclerosis (ALS4) are neurological disorders caused by mutations in the gene encoding for senataxin (SETX), a putative RNA:DNA helicase involved in transcription and in the maintenance of genome integrity. Here, using ChIP followed by high throughput sequencing (ChIP-seq), we report that senataxin is recruited at DNA double-strand breaks (DSBs) when they occur in transcriptionally active loci. Genome-wide mapping unveiled that RNA:DNA hybrids accumulate on DSB-flanking chromatin but display a narrow, DSB-induced, depletion near DNA ends coinciding with senataxin binding. Although neither required for resection nor for timely repair of DSBs, senataxin was found to promote Rad51 recruitment, to minimize illegitimate rejoining of distant DNA ends and to sustain cell viability following DSB production in active genes. Our data suggest that senataxin functions at DSBs in order to limit translocations and ensure cell viability, providing new insights on AOA2/ALS4 neuropathies.

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“…To track SETX subcellular localization, we developed a GFP-tagged, full-length expression construct. We tested if SETX might show nucleolus localization, based upon initial yeast Sen1p experimentation [26,27]. There is growing interest in the nucleolus, as disruption of this structure has been implicated in ALS linked to mutations in various RNA-binding proteins and C9orf72 dipeptide repeats [28,29].…”

Section: Setx Over-expression In Hek293a Cells Linked With Nucleolus Dissolutionmentioning

confidence: 99%

Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly

Bennett

Sopher

Spada

2020

Heliyon

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The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive SETX mutations cause a severe ataxia, known as Ataxia with Oculomotor Apraxia type 2, while dominant SETX mutations cause Amyotrophic Lateral Sclerosis type 4. SETX is a very low abundance protein, and its expression is tightly regulated, such that large increases in mRNA levels fail to significantly increase protein levels. Despite this, transient transfection in cell culture can boost SETX protein levels on an individual cell basis. Here we found that over-expression of normal SETX, but not enzymatically-dead SETX, is associated with S-phase cell-cycle arrest in HEK293A cells. As SETX interacts with the nuclear exosome to ensure degradation of incomplete RNA transcripts, and SETX localizes to sites of collision between the DNA replication machinery and the RNAP II complex, altered dosage or aberrant function of SETX may impede this process to promote S-phase cell-cycle arrest. Because neurons are enriched for long transcripts with additional antisense regulatory transcription, collisions of RNAP II complexes may occur in such post-mitotic cells, underscoring a role for SETX in maintaining neuron homeostasis.

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Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage

Cited by 15 publications

References 29 publications

Lysosomal abnormalities in hereditary spastic paraplegia types SPG 15 and SPG 11

Lysosomal abnormalities in hereditary spastic paraplegia types SPG 15 and SPG 11

Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations

Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly

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