"Major roles of pyrimidine dimers, nucleotide excision repair and ATR in the alternative splicing response to UV irradiation"

MUÑOZ MJ

Congreso; Joint Meeting of Bioscience Societies; 2017

SAIB SAIC

DNA damage caused naturally by UV light exposure in skin cells triggers not only lesion repair mechanisms but also a global gene expression response that ultimately modulates cell functions. We recently demonstrated that repair of damaged DNA by the Nucleotide Excision Repair (NER) system generates single stranded DNA intermediates that in turn activate the ataxia telangiectasia mutated and Rad3 related (ATR) kinase. Active ATR triggers global hyperphosphorylation of the Carboxyl Terminal Domain (CTD) of RNAPII major subunit affecting gene expression at the quantitative and qualitative (alternative splicing isoforms) levels (Muñoz et al., 2017). Moreover, using CRISPR-Cas9 technology, we found that ablation of XPE, a lesion recognition factor, partially decreased the UV effect on AS, further demonstrating the crosstalk between repair and gene expression (Muñoz, 2017). To pursue the idea of the repair process acting as a gene expression controller in a genotoxic scenario, we knocked-down different repair factors to evaluate repair and gene expression upon UV irradiation of skin cells. The NER factors can be divided in two groups, those in charge of lesion recognition (XPE, XPC) and those in charge of the actual repair (XPA, XPB, XPD, XPF, XPG). We found that impairment in lesion recognition (XPE, XPC) or in the actual repair (XPA, XPB) have different consequences at the gene expression level. While it is clear that all XP patients have an increased risk of developing skin cancer, some other puzzling clinical features are characteristic of the specific factor being mutated: while XPA and XPB (repair factors) patients develop blistering burns on minimal sun exposure, patients with defects in recognition (XPC and XPE) do not (DiGiovanna, 2012). Therefore we propose that some of the clinical features of XP patients are due to defects in gene expression modulation triggered by the DNA repair pathway.