In an article published in the journal Proceedings of the National Academy of Sciences (PNAS) by Dr. Carlos Fernández Tornero, principal investigator of the Group of Structure of Macromolecular Assemblies of the Centro de Investigaciones Biológicas, the mechanism by which the enzyme RNA Polymerase I gets stalled when a DNA lesion caused by exposure to ultraviolet light approaches its active site is revealed.
DNA damage threatens cell life and must be repaired to maintain genome integrity. One of the most common DNA lesions are thymine dimers deriving from exposure to ultraviolet light, such as that from the sun. During the synthesis of cellular RNA, RNA polymerases are responsible for identifying these lesions and activating their repair. Among this family of enzymes, RNA polymerase I is the most active in growing cells, so its ability to identify lesions has a decisive influence on the survival to damage caused by ultraviolet radiation.
The work, which is first authored by Marta Sanz-Murillo, characterizes the mechanism by which RNA polymerase I stalls as the lesion approaches its active site and initiates the recruitment of proteins responsible for DNA repair. Additionally, a mutational study has allowed the identification of one amino acid, among more than 5,000 constituting this complex enzyme, which contributes in an essential way to the detection of thymine dimers formed by ultraviolet light exposure.
These findings, which open the avenue to the discovery of the molecular mechanisms underlying the cellular endurance to DNA lesions, were possible thanks to the combination of in vitro enzymatic activity studies and the structure obtained by electron cryomicroscopy, a technique awarded with the Nobel Prize in Chemistry in 2017. Understanding the resistance of cells to ultraviolet light will allow the development of tools providing protection against moderate doses of sun irradiation.
This work is the result of an international collaboration between the Centro de Investigaciones Biológicas (Madrid), the University of California San Diego (La Jolla), the University of Turku (Finland), the CIC bioGUNE (Bilbao) and the CSIC institutes, Centro de Biología Molecular Severo Ochoa (Madrid) and Instituto de Biología Fundamental y Genómica (Salamanca).
This work has been selected as cover in PNAS journal no. 36:
Reference: Structural basis of RNA polymerase I stalling at UV light-induced DNA damage. Marta Sanz-Murillo, Jun Xu, Georgiy A. Belogurov, Olga Calvo, David Gil-Carton, María Moreno-Morcillo, Dong Wang, and Carlos Fernández-Tornero. PNAS (2018). DOI: 10.1073/pnas.1802626115
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