Continuous transcription initiation guarantees robust repair of all transcribed genes and regulatory regions

Anastasios Liakos, Dimitris Konstantopoulos, Matthieu D. Lavigne () and Maria Fousteri ()
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Anastasios Liakos: BSRC ‘Alexander Fleming’
Dimitris Konstantopoulos: BSRC ‘Alexander Fleming’
Matthieu D. Lavigne: BSRC ‘Alexander Fleming’
Maria Fousteri: BSRC ‘Alexander Fleming’

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Inhibition of transcription caused by DNA damage-impaired RNA polymerase II (Pol II) elongation conceals 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 lesions and limited mutagenesis, it is still unclear how this mechanism is maintained during genotoxic stress-recovery. Here we uncover a widespread gain in chromatin accessibility and preservation of the active H3K27ac mark after UV-irradiation. The concomitant increase in Pol II escape from promoter-proximal pause (PPP) sites of most active genes, PROMPTs and enhancer RNAs favors unrestrained initiation, as evidenced by the synthesis of nascent RNAs including start RNAs. Accordingly, drug-inhibition of PPP-release replenishes levels of pre-initiating Pol II at TSSs after UV. Our data show that such continuous engagement of Pol II molecules ensures maximal transcription-driven repair throughout expressed genes and regulatory loci. Importantly, revealing this unanticipated regulatory layer of UV-response provides physiological relevant traction to the emerging concept that Pol II initiation rate is determined by pause-release dynamics.

Date: 2020
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DOI: 10.1038/s41467-020-14566-9

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