Abstract
Repair of oxidative DNA damage, particularly Base Excision Repair (BER), impairment is often associated with Alzheimer’s disease pathology. Here, we aimed at investigating the complete Nucleotide Excision Repair (NER), a DNA repair pathway involved in the removal of bulky DNA adducts, status in an Alzheimer-like cell line. The level of DNA damage was quantified using mass spectrometry, NER gene expression was assessed by qPCR, and the NER protein activity was analysed through a modified version of the COMET assay. Interestingly, we found that in the presence of the Amyloid β peptide (Aβ), NER factors were upregulated at the mRNA level and that NER capacities were also specifically increased following oxidative stress. Surprisingly, NER capacities were not differentially improved following a typical NER-triggering of ultraviolet C (UVC) stress. Oxidative stress generates a differential and specific DNA damage response in the presence of Aβ. We hypothesized that the release of NER components such as DNA damage binding protein 2 (DDB2) and Xeroderma Pigmentosum complementation group C protein (XPC) following oxidative stress might putatively involve their apoptotic role rather than DNA repair function.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease, which progressively leads to massive neuronal death
We previously showed that the secretion of the AD-specific neurotoxic peptide Amyloid β peptide (Aβ) in a neuroblastoma cell line led to an overall decrease of base excision repair (BER), either at the basal level or following oxidative stress [20]
We showed that the two cell lines exhibited a similar modulation of the expression pattern upon ultraviolet C (UVC)-irradiation with overexpression of the same Nucleotide excision repair (NER) genes, especially Xeroderma Pigmentosum complementation group C protein (XPC) and DNA damage binding protein 2 (DDB2)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease, which progressively leads to massive neuronal death. AD brains exhibit a massive apoptosis, which is known to be a cellular response to excess DNA damage that triggers a programmed cell death mechanism [2]. The link between AD and accumulation of DNA damage has led several groups to study the DNA repair capacities in AD patients, mouse models and cell lines and, as a general trend, a lower ability to maintain genomic integrity was observed [3,4,5,6,7,8,9,10,11]. Cells possess several DNA repair pathways, each of them is in charge of a specific class of lesions. The base excision repair (BER) pathway is preferentially involved in removing and replacing either methylated, oxidized or deaminated (uracil) bases and single strand breaks [12].
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