An altered redox balance mediates the hypersensitivity of Cockayne syndrome primary fibroblasts to oxidative stress

Pascucci, Barbara; Lemma, Tiziana; Iorio, Egidio; Giovannini, Sara; Vaz, Bruno; Iavarone, Ivano; Calcagnile, A.; Narciso, Laura; Degan, Paolo; Roginskya, Vera; Janjic, Bratislav; Houten, Bennett Van; Stefanini, Miria; Dogliotti, Eugenia; D’Errico, Mariarosaria

doi:10.1111/j.1474-9726.2012.00815.x

Cited by 86 publications

(71 citation statements)

References 37 publications

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“…S1C). Conversely, treatment with oligomycin, an inhibitor of the mitochondrial respiratory chain, revealed significant glycolytic shifts (increased glycolysis/OXPHOS ratio) in all CS cells compared with controls, consistent with a previous report (23), but not in UV S S1VI cells, suggesting that the metabolic shift was CS-specific (Fig. 1B).…”

Section: Resultssupporting

confidence: 92%

“…Next, we elucidated the mechanism(s) that gave rise to CSA/CSB effects on HTRA2 and HTRA3. HTRA2 expression increases in tissues undergoing oxidative stress, and CS cells are hypersensitive to oxidative stress (8,23). All CS cells exhibited higher levels (1.6-to 2-fold) of ROS, evaluated with the fluorescent probe DCFDA, than those observed in controls and UV S S1VI cells (Fig.…”

Section: Resultsmentioning

confidence: 86%

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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: 92%

Section: Resultsmentioning

confidence: 86%

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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“…In UVSSA-defective cells, CSB/ERCC6 appears to be ubiquitinated and degraded after UV, likely potentiating RNA Pol II stalling and impairing recovery (Fig. 3) (Nakazawa et al 2012;Schwertman et al 2012;Zhang et al 2012 Pascucci et al 2012). Furthermore, CSA/ERCC8 and CSB/ERCC6 have been identified in mitochondria where they are thought to play a role in the repair of mtDNA, deficits of which may contribute to impaired neurogenesis and/or neurodegeneration, as discussed above for MCSZ (Kamenisch et al 2010).…”

Section: Uv-sensitive Scaffold Protein a And Uv-sensitive Syndromementioning

confidence: 89%

Diseases Associated with Defective Responses to DNA Damage

O’Driscoll

2012

Cold Spring Harbor Perspectives in Biology

106

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Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.

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“…In addition, the Csb-deficient mouse retina was found to be hypersensitive to ionizing radiation (33). Fibroblasts derived from CS-B patients are more sensitive to oxidants and are impaired in the repair of oxidatively induced DNA lesions (63,90).…”

Section: Transcription-coupled Repair: Csa Csb and Xpgmentioning

confidence: 99%

Oxidative DNA Damage and Nucleotide Excision Repair

Melis

Steeg

Luijten

2013

Antioxidants & Redox Signaling

182

145

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Significance: Oxidative DNA damage is repaired by multiple, overlapping DNA repair pathways. Accumulating evidence supports the hypothesis that nucleotide excision repair (NER), besides base excision repair (BER), is also involved in neutralizing oxidative DNA damage. Recent Advances: NER includes two distinct sub-pathways: transcription-coupled NER (TC-NER) and global genome repair (GG-NER). The CSA and CSB proteins initiate the onset of TC-NER. Recent findings show that not only CSB, but also CSA is involved in the repair of oxidative DNA lesions, in the nucleus as well as in mitochondria. The XPG protein is also of importance for the removal of oxidative DNA lesions, as it may enhance the initial step of BER. Substantial evidence exists that support a role for XPC in NER and BER. XPC deficiency not only results in decreased repair of oxidative lesions, but has also been linked to disturbed redox homeostasis. Critical Issues: The role of NER proteins in the regulation of the cellular response to oxidative (mitochondrial and nuclear) DNA damage may be the underlying mechanism of the pathology of accelerated aging in Cockayne syndrome patients, a driving force for internal cancer development in XP-A and XP-C patients, and a contributor to the mixed exhibited phenotypes of XP-G patients. Future Directions: Accumulating evidence indicates that DNA repair factors can be involved in multiple DNA repair pathways. However, the distinct detailed mechanism and consequences of these additional functions remain to be elucidated and can possibly shine a light on clinically related issues.

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An altered redox balance mediates the hypersensitivity of Cockayne syndrome primary fibroblasts to oxidative stress

Cited by 86 publications

References 37 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

Diseases Associated with Defective Responses to DNA Damage

Oxidative DNA Damage and Nucleotide Excision Repair

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