» Articles » PMID: 29233992

Global Unleashing of Transcription Elongation Waves in Response to Genotoxic Stress Restricts Somatic Mutation Rate

Overview
Journal Nat Commun
Specialty Biology
Date 2017 Dec 14
PMID 29233992
Citations 41
Authors
Affiliations
Soon will be listed here.
Abstract

Complex molecular responses preserve gene expression accuracy and genome integrity in the face of environmental perturbations. Here we report that, in response to UV irradiation, RNA polymerase II (RNAPII) molecules are dynamically and synchronously released from promoter-proximal regions into elongation to promote uniform and accelerated surveillance of the whole transcribed genome. The maximised influx of de novo released RNAPII correlates with increased damage-sensing, as confirmed by RNAPII progressive accumulation at dipyrimidine sites and by the average slow-down of elongation rates in gene bodies. In turn, this transcription elongation 'safe' mode guarantees efficient DNA repair regardless of damage location, gene size and transcription level. Accordingly, we detect low and homogenous rates of mutational signatures associated with UV exposure or cigarette smoke across all active genes. Our study reveals a novel advantage for transcription regulation at the promoter-proximal level and provides unanticipated insights into how active transcription shapes the mutagenic landscape of cancer genomes.

Citing Articles

Translational Approach to Social Isolation During a Global Pandemic: Hippocampal Somatic Mutation and Stress.

Lee B, Maeng S, Seo Y, Jung S, Im S, Choi H Psychiatry Investig. 2025; 21(12):1360-1371.

PMID: 39757814 PMC: 11704808. DOI: 10.30773/pi.2024.0178.


Cockayne syndrome B protein is implicated in transcription and associated chromatin dynamics in homeostatic and genotoxic conditions.

Liakos A, Ntakou-Zamplara K, Angelova N, Konstantopoulos D, Synacheri A, Spyropoulou Z Aging Cell. 2024; 24(1):e14341.

PMID: 39370748 PMC: 11874911. DOI: 10.1111/acel.14341.


From silence to symphony: transcriptional repression and recovery in response to DNA damage.

Ajit K, Gullerova M Transcription. 2024; 15(3-5):161-175.

PMID: 39353089 PMC: 11810087. DOI: 10.1080/21541264.2024.2406717.


Post-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress.

Talukdar P, Pal S, Biswas D Nat Commun. 2024; 15(1):4128.

PMID: 38750015 PMC: 11096357. DOI: 10.1038/s41467-024-48530-8.


Gene architecture is a determinant of the transcriptional response to bulky DNA damages.

Merav M, Bitensky E, Heilbrun E, Hacohen T, Kirshenbaum A, Golan-Berman H Life Sci Alliance. 2024; 7(3).

PMID: 38167611 PMC: 10761554. DOI: 10.26508/lsa.202302328.


References
1.
You Y, Lee D, Yoon J, Nakajima S, Yasui A, Pfeifer G . Cyclobutane pyrimidine dimers are responsible for the vast majority of mutations induced by UVB irradiation in mammalian cells. J Biol Chem. 2001; 276(48):44688-94. DOI: 10.1074/jbc.M107696200. View

2.
Pleasance E, Cheetham R, Stephens P, McBride D, Humphray S, Greenman C . A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2009; 463(7278):191-6. PMC: 3145108. DOI: 10.1038/nature08658. View

3.
Haradhvala N, Polak P, Stojanov P, Covington K, Shinbrot E, Hess J . Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair. Cell. 2016; 164(3):538-49. PMC: 4753048. DOI: 10.1016/j.cell.2015.12.050. View

4.
Mokry M, Hatzis P, Schuijers J, Lansu N, Ruzius F, Clevers H . Integrated genome-wide analysis of transcription factor occupancy, RNA polymerase II binding and steady-state RNA levels identify differentially regulated functional gene classes. Nucleic Acids Res. 2011; 40(1):148-58. PMC: 3245935. DOI: 10.1093/nar/gkr720. View

5.
Smith E, Shilatifard A . Transcriptional elongation checkpoint control in development and disease. Genes Dev. 2013; 27(10):1079-88. PMC: 3672643. DOI: 10.1101/gad.215137.113. View