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Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):8972-8977. doi: 10.1073/pnas.1802626115. Epub 2018 Aug 20.

Structural basis of RNA polymerase I stalling at UV light-induced DNA damage.

Author information

1
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas (CSIC), 28040 Madrid, Spain.
2
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0625.
3
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093-0625.
4
Department of Biochemistry, University of Turku, FIN-20014, Turku, Finland.
5
Instituto de Biología Funcional y Genómica, CSIC-Universidad de Salamanca, 37007 Salamanca, Spain.
6
Structural Biology Unit, Cooperative Center for Research in Biosciences (CIC bioGUNE), 48160 Derio, Spain.
7
Centro de Biología Molecular Severo Ochoa, CSIC, 28049 Madrid, Spain.
8
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0625; dongwang@ucsd.edu cftornero@cib.csic.es.
9
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas (CSIC), 28040 Madrid, Spain; dongwang@ucsd.edu cftornero@cib.csic.es.

Abstract

RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) to produce the ribosomal RNA (rRNA) precursor, which accounts for up to 60% of the total transcriptional activity in growing cells. Pol I monitors rDNA integrity and influences cell survival, but little is known about how this enzyme processes UV-induced lesions. We report the electron cryomicroscopy structure of Pol I in an elongation complex containing a cyclobutane pyrimidine dimer (CPD) at a resolution of 3.6 Å. The structure shows that the lesion induces an early translocation intermediate exhibiting unique features. The bridge helix residue Arg1015 plays a major role in CPD-induced Pol I stalling, as confirmed by mutational analysis. These results, together with biochemical data presented here, reveal the molecular mechanism of Pol I stalling by CPD lesions, which is distinct from Pol II arrest by CPD lesions. Our findings open the avenue to unravel the molecular mechanisms underlying cell endurance to lesions on rDNA.

KEYWORDS:

DNA repair; RNA polymerase I; UV damage; cyclobutane pyrimidine dimers; transcription

PMID:
30127008
PMCID:
PMC6130403
[Available on 2019-03-04]
DOI:
10.1073/pnas.1802626115
[Indexed for MEDLINE]

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