Gene expression misregulation in DNA repair deficient cells

ADRIÁN CAMBINDO BOTTO; JUAN C. MUÑOZ; LUCIANA GIONO; NICOLAS NIETO MORENO; ALBERTO R KORNBLIHTT; MANUEL J. MUÑOZ

Congreso; XXII International Congress of Genetics; 2018

DNA damage caused naturally by UV light exposure in skin cells triggers not onlylesion repair mechanisms but also a global gene expression response thatultimately modulates cell functions. We recently demonstrated that repair ofdamaged DNA by the Nucleotide Excision Repair (NER) system generates singlestranded DNA intermediates that in turn activate the ATR kinase. Active ATRtriggers global hyperphosphorylation of RNAPII major subunit affecting geneexpression at the quantitative and qualitative (alternative splicing isoforms)levels. Moreover, using CRISPR-Cas9 technology, we found that ablation ofXPE, a lesion recognition factor, partially decreased the UV effect on AS, furtherdemonstrating the crosstalk between repair and gene expression (Muñoz, 2017).To pursue the idea of the repair process acting as a gene expression controller ina genotoxic scenario, we knocked-down different repair factors to evaluate repairand gene expression upon UV irradiation of skin cells. The NER factors can bedivided in two groups, those in charge of lesion recognition (XPE/XPC) and thosein charge of the actual repair (XPA/XPB/XPD/XPF/XPG). We found thatimpairment in lesion recognition or in the actual repair have differentconsequences at the gene expression level.While it is clear that all XP patients have an increased risk of developing skincancer, some other puzzling clinical features are characteristic of the specificfactor being mutated. Therefore we propose that some of the clinical features ofXP patients are due to defects in gene expression modulation triggered by theDNA repair pathway.