Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage

Cleaver, James E.; Brennan-Minnella, Angela M.; Swanson, Raymond A.; Fong, Ka Wing; Chen, Junjie; Chou, Kai Ming; Chen, Yih Wen; Revet, Ingrid; Bezrookove, Vladimir

doi:10.1073/pnas.1414135111

Cited by 61 publications

(45 citation statements)

References 45 publications

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“…5A and Fig. S5A), compatibly with a previous report (9). Moreover, all patientderived cells displayed very high hypoxia-inducible factor-1 (HIF1α) mRNA levels, which are induced by high ROS content (39), compared with controls (Fig.…”

Section: Resultssupporting

confidence: 89%

“…Comparison of these two types of patient' cells indicates that the impaired UV response was uncoupled from oxidative stress and premature aging. In agreement with this finding, higher levels of reactive oxygen species (ROS) were recently reported in mitochondria from CS compared with UV S S and healthy cells (9). CSA and CSB also act as transcription factors, and CSB has been proposed to remodel chromatin (10)(11)(12).…”

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confidence: 58%

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Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome

Châtre

Biard

Sarasin

et al. 2015

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

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UV-sensitive syndrome (UV S S) and Cockayne syndrome (CS) are human disorders caused by CSA or CSB gene mutations; both conditions cause defective transcription-coupled repair and photosensitivity. Patients with CS also display neurological and developmental abnormalities and dramatic premature aging, and their cells are hypersensitive to oxidative stress. We report CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1), due to HTRA3 serine protease accumulation in CS, but not in UV s S or control fibroblasts. Inhibition of serine proteases restored physiological POLG1 levels in either CS fibroblasts and in CSB-silenced cells. Moreover, patient-derived CS cells displayed greater nitroso-redox imbalance than UV S S cells. Scavengers of reactive oxygen species and peroxynitrite normalized HTRA3 and POLG1 levels in CS cells, and notably, increased mitochondrial oxidative phosphorylation, which was altered in CS cells. These data reveal critical deregulation of proteases potentially linked to progeroid phenotypes in CS, and our results suggest rescue strategies as a therapeutic option.Cockayne syndrome | premature ageing | serine protease | DNA polymerase gamma | mtSSB

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Section: Resultssupporting

confidence: 89%

supporting

confidence: 58%

Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome

Châtre

Biard

Sarasin

et al. 2015

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

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“…Because G:C→T:A mutations are a signature of mutagenesis induced by 8-oxo-dG, the most common oxidative lesion in cells (37), this observation alludes to CSB's additional role in oxidative DNAdamage repair (21)(22)(23), loss of which could result in increased oxidative damage-induced mutagenesis. We previously reported that CSB interacts with complex I of the mitochondria to quench surplus reactive oxygen species (38). Given the neurological involvement in CS, further studies on the mutagenic consequences of oxidative DNA damage may be worthwhile for understanding the pathologies seen in CS.…”

Section: Discussionmentioning

confidence: 99%

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency

Reid-Bayliss

Arron

Loeb

et al. 2016

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

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Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are human photosensitive diseases with mutations in the nucleotide excision repair (NER) pathway, which repairs DNA damage from UV exposure. CS is mutated in the transcription-coupled repair (TCR) branch of the NER pathway and exhibits developmental and neurological pathologies. The XP-C group of XP patients have mutations in the global genome repair (GGR) branch of the NER pathway and have a very high incidence of UV-induced skin cancer. Cultured cells from both diseases have similar sensitivity to UV-induced cytotoxicity, but CS patients have never been reported to develop cancer, although they often exhibit photosensitivity. Because cancers are associated with increased mutations, especially when initiated by DNA damage, we examined UV-induced mutagenesis in both XP-C and CS cells, using duplex sequencing for high-sensitivity mutation detection. Duplex sequencing detects rare mutagenic events, independent of selection and in multiple loci, enabling examination of all mutations rather than just those that confer major changes to a specific protein. We found telomerase-positive normal and CS-B cells had increased background mutation frequencies that decreased upon irradiation, purging the population of subclonal variants. Primary XP-C cells had increased UV-induced mutation frequencies compared with normal cells, consistent with their GGR deficiency. CS cells, in contrast, had normal levels of mutagenesis despite their TCR deficiency. The lack of elevated UV-induced mutagenesis in CS cells reveals that their TCR deficiency, although increasing cytotoxicity, is not mutagenic. Therefore the absence of cancer in CS patients results from the absence of UV-induced mutagenesis rather than from enhanced lethality.

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“…Moreover, using a host cell reactivation (HCR) assay in which undamaged cells were transfected with plasmids treated prior to transfection to induce the oxidized bases, 8-oxoG or thymine glycol, we have demonstrated that expression of the plasmid-coded lacZ reporter gene is defective in CS cells but not in UV S S cells [36]. A possible explanation for these puzzling results is that the CS defect not only eliminates TCR but that it affects other cellular functions such as transcriptional bypass of oxidative damage [38–41], processing of oxidative damage in mitochondria [42–45] or defective neurogenesis [46, 47]…”

Section: Dna Repair and Photosensitivitymentioning

confidence: 99%

Photosensitive human syndromes

Spivak¹,

Hanawalt²

2015

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Photosensitivity in humans can result from defects in repair of light-induced DNA lesions, from photoactivation of chemicals (including certain medications) with sunlight to produce toxic mediators, and by immune reactions to sunlight exposures. Deficiencies in DNA repair and the processing of damaged DNA during replication and transcription may result in mutations and genomic instability. We will review current understanding of photosensitivity to short wavelength ultraviolet light (UV) due to genetic defects in particular DNA repair pathways; deficiencies in some are characterized by an extremely high incidence of cancer in sun-exposed tissues, while in others no cancers have been reported.

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Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage

Cited by 61 publications

References 45 publications

Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome

Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency

Photosensitive human syndromes

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