Integrated multiomic analysis identifies functional epigenetic signatures regulating nucleotide excision repair (RNA-seq)

Transcription-coupled nucleotide excision repair (TC-NER) is promptly triggered by 'local' elongating RNAP II molecules encountering DNA adducts such as cyclobutane pyrimidine dimers (CPD) induced by ultraviolet light and speeds up removing and repair in transcribed loci. Genome-wide measurements have revealed a dramatic shutdown of global transcription with a few exceptions of individual genes that are consequently highly upregulated by DNA damage. Deciphering the underlying mechanisms of the multifaceted transcriptional response always comprises one of the most fascinating frontiers in DNA repair research. Recent reports have revealed that persistent RNAP II initiation at the transcription start site of active regulatory regions with the continuous synthesis of start-RNAs guarantee sufficient scanning and repair of the whole transcribed genome, although transcription elongation drastically slows down shortly after genotoxic stress. Furthermore, a recent study found that RNA is extremely rapidly m6A methylated by METTL3 in response to UV irradiation which is crucial for recruitment of Pol k to DNA damage sites and subsequently mediates TC-NER. Together, these findings substantiate the molecular processes underlying the transcription-coordinated cellular response upon genotoxic stress might be more complex than previously believed. Unfortunately, all these findings merely focused on the early phase of recovery (within 4 hr after DNA damage). It remains to be determined how accessible chromatin reconfigures and regulates transcriptional programs in UV-induced DNA damage repair. It is also unclear whether the dynamics of gene expression are associated with other epigenomic reconstruction events such as global DNA methylation and demethylation. Moreover, the roles of internal messenger RNA modifications like N6-methyladenosine in TC-NER are poorly understood. Our integrative analyses provide a comprehensive view of the spatio-temporal chromatin configuration and epigenetic characterizations that accompanies TC-NER.