Abstract
Cockayne Syndrome (CS) is an autosomal recessive neurodegenerative premature aging disorder associated with defects in nucleotide excision repair (NER). Cells from CS patients, with mutations in CSA or CSB genes, present elevated levels of reactive oxygen species (ROS) and are defective in the repair of a variety of oxidatively generated DNA lesions. In this study, six purine lesions were ascertained in wild type (wt) CSA, defective CSA, wtCSB and defective CSB-transformed fibroblasts under different oxygen tensions (hyperoxic 21%, physioxic 5% and hypoxic 1%). In particular, the four 5′,8-cyclopurine (cPu) and the two 8-oxo-purine (8-oxo-Pu) lesions were accurately quantified by LC-MS/MS analysis using isotopomeric internal standards after an enzymatic digestion procedure. cPu levels were found comparable to 8-oxo-Pu in all cases (3–6 lesions/106 nucleotides), slightly increasing on going from hyperoxia to physioxia to hypoxia. Moreover, higher levels of four cPu were observed under hypoxia in both CSA and CSB-defective cells as compared to normal counterparts, along with a significant enhancement of 8-oxo-Pu. These findings revealed that exposure to different oxygen tensions induced oxidative DNA damage in CS cells, repairable by NER or base excision repair (BER) pathways. In NER-defective CS patients, these results support the hypothesis that the clinical neurological features might be connected to the accumulation of cPu. Moreover, the elimination of dysfunctional mitochondria in CS cells is associated with a reduction in the oxidative DNA damage.
Highlights
Hypoxia is a common condition in many diseases
In this study we provide for the first time the connection between oxygen concentration and DNA
The abundance of an important family of oxidatively induced DNA lesions was investigated in DNA repair-deficient cell lines such as CSA and CSB, cultured under various oxygen conditions
Summary
Hypoxia is a common condition in many diseases. Reduced oxygen supply has been observed during the aging process as well as the onset of neurodegeneration [1]. Hypoxia can increase Aβ production [4], enhance tau phosphorylation [5], induce neuroinflammation [6], increase reactive oxygen species generation [2], and elicit abnormal mitochondrial function [7]. Enhancing α-synuclein expression and aggregation, hypoxia is a potential cause of Parkinson disease [8] and it is a causative factor of both the onset and progression of amyotrophic lateral sclerosis [9]. A role of hypoxia in multiple sclerosis is observed [10]
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