The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase.

Autor: Shigdel UK; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.; LifeMine Therapeutics, 430 East 29th Street, Suite 830, New York, NY, 10016, USA., Ovchinnikov V; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA., Lee SJ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.; Beam Therapeutics, 26 Landsdowne Street, 2nd Floor, Cambridge, MA, 02139, USA., Shih JA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.; Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA., Karplus M; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.; Laboratoire de Chime Biophysique, Institut de Science et d'Ingénierie Supramoléculaires, Université de Strasbourg, 67000, Strasbourg, France., Nam K; Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, 76019-0065, USA. kwangho.nam@uta.edu.; Department of Chemistry, Umeå University, Umeå, SE 901 87, Sweden. kwangho.nam@uta.edu., Verdine GL; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. Gregory_verdine@harvard.edu.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA. Gregory_verdine@harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Sep 07; Vol. 11 (1), pp. 4437. Date of Electronic Publication: 2020 Sep 07.
DOI: 10.1038/s41467-020-18290-2
Abstrakt: Efficient search for DNA damage embedded in vast expanses of the DNA genome presents one of the greatest challenges to DNA repair enzymes. We report here crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, that interact with the DNA containing the damaged base oxoG and the normal base G while they are nested in the DNA helical stack. The structures reveal that hOGG1 engages the DNA using different protein-DNA contacts from those observed in the previously determined lesion recognition complex and other hOGG1-DNA complexes. By applying molecular dynamics simulations, we have determined the pathways taken by the lesion and normal bases when extruded from the DNA helix and their associated free energy profiles. These results reveal how the human oxoG DNA glycosylase hOGG1 locates the lesions inside the DNA helix and facilitates their extrusion for repair.
Databáze: MEDLINE