"Gene expression misregulation in DNA repair deficient cells"

MANUEL J. MUÑOZ

Congreso; 6th Meeting of Fundamental Aspects of DNA Repair and Mutagenesis- 6th FARM-DNA; 2018

GENE EXPRESSION MISREGULATION IN DNA REPAIR DEFICIENT CELLSAdrian Cambindo Botto1, Juan C. Muñoz1, Luciana Giono1, Nicolás Nieto Moreno1, Alberto R. Kornblihtt1 & Manuel J. Muñoz1, 21 Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET) and Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina. 2 Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139 Milan, Italy. 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 ATR kinase. Active ATR triggers global hyperphosphorylation of RNAPII major subunit affecting gene expression at the quantitative and qualitative (alternative splicing isoforms) levels. 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 or in the actual repair 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. 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.