Abstract
The kinetics of DNA repair and RNA synthesis recovery in human cells following UV-irradiation were assessed using nascent RNA Bru-seq and quantitative long PCR. It was found that UV light inhibited transcription elongation and that recovery of RNA synthesis occurred as a wave in the 5′-3′ direction with slow recovery and TC-NER at the 3′ end of long genes. RNA synthesis resumed fully at the 3′-end of genes after a 24 h recovery in wild-type fibroblasts, but not in cells deficient in transcription-coupled nucleotide excision repair (TC-NER) or global genomic NER (GG-NER). Different transcription recovery profiles were found for individual genes but these differences did not fully correlate to differences in DNA repair of these genes. Our study gives the first genome-wide view of how UV-induced lesions affect transcription and how the recovery of RNA synthesis of large genes are particularly delayed by the apparent lack of resumption of transcription by arrested polymerases.
Highlights
Ultraviolet light (UV) from sunlight has through evolutionary time challenged all living organisms by damaging DNA
It is well known that UV-irradiation effectively inhibits the synthesis of nascent RNA by blocking transcription elongation at sites of cyclobutane pyrimidine dimers (CPD) and 6–4 photoproducts [27]
Whether transcription-coupled nucleotide excision repair (TC-NER) works on all protein-coding and non-coding genes transcribed by RNA polymerase II is not known
Summary
Ultraviolet light (UV) from sunlight has through evolutionary time challenged all living organisms by damaging DNA. It has been shown that blocked RNA polymerases recruit nucleotide excision repair factors in a CSA- and CSBmediated manner allowing for a preferential repair of active genes [7] in a strand-specific manner [8]. This form of repair, transcription-coupled nucleotide excision repair (TCNER), has been assessed in mammalian genes including DHFR, JUN, MYC and CDC2 [9,10,11] and RBP2, URA3, MFA2 and GAL1–10 in yeast [12,13,14]. Based on these results from a limited number of genes, it has been assumed that TC-NER operates on all transcribing genes in the genome
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