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

Shigdel, Uddhav K.; Ovchinnikov, Victor; Lee, Seung-Joo; Shih, Jenny A.; Karplus, Martin; Nam, Kwangho; Verdine, Gregory L.

doi:10.1038/s41467-020-18290-2

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

Journal Article · Sun Sep 27 00:00:00 EDT 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-18290-2· OSTI ID:1701771

Shigdel, Uddhav K. ^[1]; Ovchinnikov, Victor ^[1]; Lee, Seung-Joo ^[1]; Shih, Jenny A. ^[1]; Karplus, Martin ^[2]; Nam, Kwangho ^[3]; Verdine, Gregory L. ^[1]

Harvard Univ., Cambridge, MA (United States)
Harvard Univ., Cambridge, MA (United States); Univ. de Strasbourg (France)
Univ. of Texas, Arlington, TX (United States); Umea Univ. (Sweden)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231; AC05-00OR22725

OSTI ID:: 1701771

Journal Information:: Nature Communications, Journal Name: Nature Communications Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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