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dc.contributor.authorTsutakawa, Susan E.
dc.contributor.authorSarker, Altaf H.
dc.contributor.authorNg, Clifford
dc.contributor.authorArvai, Andrew S.
dc.contributor.authorShin, David S.
dc.contributor.authorShih, Brian
dc.contributor.authorJiang, Shuai
dc.contributor.authorThwin, Aye C.
dc.contributor.authorTsai, Miaw-Sheue
dc.contributor.authorWillcox, Alexandra
dc.contributor.authorHer, Mai Zong
dc.contributor.authorTrego, Kelly S.
dc.contributor.authorRaetz, Alan G.
dc.contributor.authorRosenberg, Daniel
dc.contributor.authorBacolla, Albino
dc.contributor.authorHammel, Michal
dc.contributor.authorGriffith, Jack D.
dc.contributor.authorCooper, Priscilla K.
dc.contributor.authorTainer, John A.
dc.date.accessioned2020-06-16T13:29:46Z
dc.date.available2020-06-16T13:29:46Z
dc.date.issued2020-06-10
dc.identifier.citationTsutakawa, S. E., Sarker, A. H., Ng, C., Arvai, A. S., Shin, D. S., Shih, B., … Tainer, J. A. (2020). Human XPG nuclease structure, assembly, and activities with insights for neurodegeneration and cancer from pathogenic mutations. Proceedings of the National Academy of Sciences, 201921311. doi:10.1073/pnas.1921311117
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.doi10.1073/pnas.1921311117
dc.identifier.urihttp://hdl.handle.net/10754/663619
dc.description.abstractXeroderma pigmentosum group G (XPG) protein is both a functional partner in multiple DNA damage responses (DDR) and a pathway coordinator and structure-specific endonuclease in nucleotide excision repair (NER). Different mutations in the XPG gene ERCC5 lead to either of two distinct human diseases: Cancer-prone xeroderma pigmentosum (XP-G) or the fatal neurodevelopmental disorder Cockayne syndrome (XP-G/CS). To address the enigmatic structural mechanism for these differing disease phenotypes and for XPG’s role in multiple DDRs, here we determined the crystal structure of human XPG catalytic domain (XPGcat), revealing XPG-specific features for its activities and regulation. Furthermore, XPG DNA binding elements conserved with FEN1 superfamily members enable insights on DNA interactions. Notably, all but one of the known pathogenic point mutations map to XPGcat, and both XP-G and XP-G/CS mutations destabilize XPG and reduce its cellular protein levels. Mapping the distinct mutation classes provides structure-based predictions for disease phenotypes: Residues mutated in XP-G are positioned to reduce local stability and NER activity, whereas residues mutated in XP-G/CS have implied long-range structural defects that would likely disrupt stability of the whole protein, and thus interfere with its functional interactions. Combined data from crystallography, biochemistry, small angle X-ray scattering, and electron microscopy unveil an XPG homodimer that binds, unstacks, and sculpts duplex DNA at internal unpaired regions (bubbles) into strongly bent structures, and suggest how XPG complexes may bind both NER bubble junctions and replication forks. Collective results support XPG scaffolding and DNA sculpting functions in multiple DDR processes to maintain genome stability.
dc.description.sponsorshipWe thank the researchers, patients, and families who have critically contributed to defining the genetic basis for xeroderma pigmentosum group G (XPG) pathophysiology and its window into XPG biology; Steffen Emmert for providing primary patient cells XP72MA, XP165MA, and XP40GO; and Samir Hamdan and members of the Structural Biology of DNA Repair program, including Patrick Sung and Orlando Schärer, for comments. Work on XPG was supported by National Cancer Institute P01 CA092584 (to S.E.T., P.K.C., and J.A.T.), R35 CA220430 (to J.A.T.); NIH R01GM110387 (to S.E.T.), NIH P01 AG017242 and R01 ES019935 (to P.K.C.), NIH R01GM31819 and R01 ES013773 (to J.D.G.), NIH T32 AG000266 (to A.G.R.); and King Abdullah University of Science and Technology CRG3 (to J.A.T.). J.A.T. is a Cancer Prevention and Research Institute of Texas Scholar in Cancer Research and acknowledges support by a Robert A. Welch Chemistry Chair. X-ray diffraction data were collected at the Stanford Synchrotron Radiation Laboratory, supported by the Department of Energy (DOE), Office of Biological and Environmental Research, NIH, National Center for Research Resources, Biomedical Technology Program, and the National Institute of General Medical Sciences, and at Advanced Light Source SIBYLS Beamline 12.3.1, supported by NIH project ALS-ENABLE (P30 GM124169) and the Integrated Diffraction Analysis Technologies program of the US DOE Office of Biological and Environmental Research.
dc.publisherProceedings of the National Academy of Sciences
dc.relation.urlhttp://www.pnas.org/lookup/doi/10.1073/pnas.1921311117
dc.rightsArchived with thanks to Proceedings of the National Academy of Sciences
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleHuman XPG nuclease structure, assembly, and activities with insights for neurodegeneration and cancer from pathogenic mutations
dc.typeArticle
dc.identifier.journalProceedings of the National Academy of Sciences
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionMolecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
dc.contributor.institutionBiological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
dc.contributor.institutionIntegrative Structural & Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.
dc.contributor.institutionLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599.
dc.contributor.institutionDepartment of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
dc.contributor.institutionDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
dc.identifier.pages201921311
dc.date.published-online2020-06-10
dc.date.published-print2020-06-23


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