Variable interplay of UV-induced DNA damage and repair at transcription factor binding sites

Abstract

Llocs d’unió; Dany en l'ADN; Factor de transcripció

Sitios de unión; Daño en el ADN; Factor de transcripcion

Binding sites; Dna damage; Transcription factor

An abnormally high rate of UV-light related mutations appears at transcription factor binding sites (TFBS) across melanomas. The binding of transcription factors (TFs) to the DNA impairs the repair of UV-induced lesions and certain TFs have been shown to increase the rate of generation of these lesions at their binding sites. However, the precise contribution of these two elements to the increase in mutation rate at TFBS in these malignant cells is not understood. Here, exploiting nucleotide-resolution data, we computed the rate of formation and repair of UV-lesions within the binding sites of TFs of different families. We observed, at certain dipyrimidine positions within the binding site of TFs in the Tryptophan Cluster family, an increased rate of formation of UV-induced lesions, corroborating previous studies. Nevertheless, across most families of TFs, the observed increased mutation rate within the entire DNA region covered by the protein results from the decreased repair efficiency. While the rate of mutations across all TFBS does not agree with the amount of UV-induced lesions observed immediately after UV exposure, it strongly agrees with that observed after 48 h. This corroborates the determinant role of the impaired repair in the observed increase of mutation rate.

N.L.-B. acknowledges funding from the European Research Council [consolidator grant 682398]; Spanish Ministry of Economy and Competitiveness [SAF2015-66084-R, MINECO/FEDER to U.E.]; IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya); R.S. acknowledges funding support from the National Centre for Biological Sciences (NCBS-TIFR), Bangalore, India. Funding for open access charge: Spanish Ministry of Economy and Competitiveness.