Continuous transcription initiation guarantees robust repair of transcribed genes and regulatory regions in response to DNA damage
Anastasios Liakos, Dimitris Konstantopoulos, Matthieu D. Lavigne, Maria Fousteri
Received Date: 11th July 19
Inhibition of transcription elongation caused by DNA damage-impaired RNA polymerase II (Pol II) is found to conceal a local increase in de novo transcription, slowly progressing from Transcription Start Sites (TSSs) to gene ends. Although associated with accelerated repair of Pol II-encountered damages and limited mutagenesis, it is still unclear how this mechanism is maintained during recovery from genotoxic stress. Here we uncover a surprising widespread gain in chromatin accessibility and preservation of the active histone mark H3K27ac after UV-irradiation. We show that the concomitant increase in Pol II release from promoter-proximal pause (PPP) sites of most active genes, PROMoter uPstream Transcripts (PROMPTs) and enhancer RNAs (eRNAs) favors unrestrained initiation, as demonstrated by the synthesis of short nascent RNAs, including TSS-associated RNAs (start-RNAs). In accordance, drug-inhibition of the transition into elongation replenished the post-UV reduced levels of pre-initiating Pol II at TSSs. Continuous engagement of new Pol II thus ensures maximal transcription-driven DNA repair of active genes and non-coding regulatory loci. Together, our results reveal an unanticipated layer regulating the UV-triggered transcriptional-response and provide physiologically relevant traction to the emerging concept that transcription initiation rate is determined by Pol II pause-release dynamics.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.