What happens at the lesion does not stay at the lesion: Transcription-coupled nucleotide excision repair and the effects of DNA damage on transcription in cis and trans
Unperturbed transcription of eukaryotic genes by RNA polymerase II (Pol II) is crucial for proper cell function and tissue homeostasis. However, the DNA template of Pol II is continuously challenged by damaging agents that can result in transcription impediment. Stalling of Pol II on transcription-blocking lesions triggers a highly orchestrated cellular response to cope with these cytotoxic lesions. One of the first lines of defense is the transcription-coupled nucleotide excision repair (TC-NER) pathway that specifically removes transcription-blocking lesions thereby safeguarding unperturbed gene expression. In this perspective, we outline recent data on how lesion-stalled Pol II initiates TC-NER and we discuss new mechanistic insights in the TC-NER reaction, which have resulted in a better understanding of the causative-linked Cockayne syndrome and UV-sensitive syndrome. In addition to these direct effects on lesion-stalled Pol II (effects in cis), accumulating evidence shows that transcription, and particularly Pol II, is also affected in a genome-wide manner (effects in trans). We will summarize the diverse consequences of DNA damage on transcription, including transcription inhibition, induction of specific transcriptional programs and regulation of alternative splicing. Finally, we will discuss the function of these diverse cellular responses to transcription-blocking lesions and their consequences on the process of transcription restart. This resumption of transcription, which takes place either directly at the lesion or is reinitiated from the transcription start site, is crucial to maintain proper gene expression following removal of the DNA damage.
|DNA damage, RNA polymerase II, Transcription inhibition, Transcription restart, Transcription-coupled nucleotide excision repair|
|D N A Repair|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Geijer, M.E. (Marit E.), & Marteijn, J.A. (2018). What happens at the lesion does not stay at the lesion: Transcription-coupled nucleotide excision repair and the effects of DNA damage on transcription in cis and trans. D N A Repair. doi:10.1016/j.dnarep.2018.08.007