@article{4c9ddbe40ba14345b8407f552e74cac7,
title = "Cryo-EM structure of the human Sirtuin 6–nucleosome complex",
abstract = "Sirtuin 6 (SIRT6) is a multifaceted protein deacetylase/deacylase and a major target for small-molecule modulators of longevity and cancer. In the context of chromatin, SIRT6 removes acetyl groups from histone H3 in nucleosomes, but the molecular basis for its nucleosomal substrate preference is unknown. Our cryo–electron microscopy structure of human SIRT6 in complex with the nucleosome shows that the catalytic domain of SIRT6 pries DNA from the nucleosomal entry-exit site and exposes the histone H3 N-terminal helix, while the SIRT6 zinc-binding domain binds to the histone acidic patch using an arginine anchor. In addition, SIRT6 forms an inhibitory interaction with the C-terminal tail of histone H2A. The structure provides insights into how SIRT6 can deacetylate both H3 K9 and H3 K56.",
author = "Chio, {Un Seng} and Othman Rechiche and Bryll, {Alysia R.} and Jiang Zhu and Leith, {Erik M.} and Feldman, {Jessica L.} and Peterson, {Craig L.} and Song Tan and Armache, {Jean Paul}",
note = "Funding Information: Acknowledgments:W ethankS.-Y .KuanandE.BaronatPennStatefornucleosome preparations,A.WieratNCIandT .Humphre ysatPNCCforassistancewithEMdatacollection, J.ChoandC.BatorofthePennStateCryo-ElectronMicroscopyFacilityforassistancewithEM screeninganddatacollection,andJ.GrayatPennStateforassistancewithtrainingontheT20 fornegativestainEM.Funding:ThisworkwassupportedbyNationalInstitutesofHealth(NIH) grantF32GM137463(U.S.C.),NIHgrantT32BM107000(A.R.B.),NIHgrantR35GM122519(C.L.P .), andNIHgrantR35GM127034(S.T .). Researchreportedinthispublicationwassupportedbythe OfficeoftheDirector,NIH,underawardnumberS10OD026822-01.Thisprojectisfunded,in part,underagrantfromthePennsylvaniaDepartmentofHealthusingTobaccoCUREFunds. The Department specifically disclaims responsibility for any analyses, interpretations or conclusion. This research was, in part, supported by the National Cancer Institute{\textquoteright}s National Cryo-EMFacilityattheFrederickNationalLaboratoryforCancerResearchundercontract HSSN261200800001E. A portion of this research was supported by NIH grant U24GM129547 andperformedatthePNCCatOHSUandaccessedthroughEMSL,aDOEOfficeofScienceUser FacilitysponsoredbytheOfficeofBiologicalandEnvironmentalResearch.Thefiguresforthis manuscriptweregeneratedusingPyMOLandUCSFChimeraX.UCSFChimeraXisdevelopedby theResourceforBiocomputing,Visualization,andInformaticsattheUniversityofCalifornia, SanFrancisco,withsupportfromNIHR01-GM129325andtheOfficeofCyberInfrastructureand ComputationalBiology,NationalInstituteofAllergyandInfectiousDiseases.Author contributions:Conceptualization:C.L.P ., S.T ., andJ.-P .A. Methodology:U.S.C.,O.R.,A.R.B.,J.Z., E.M.L.,J.L.F ., C.L.P ., S.T ., andJ.-P .A. Investigation:U.S.C.,O.R.,A.R.B.,J.Z.,E.M.L.,J.L.F ., andJ.-P .A. Visualization:S.T .andJ.-P .A. Fundingacquisition:U.S.C.,C.L.P ., S.T ., andJ.-P .A. Project administration:C.L.P ., S.T ., andJ.-P .A. Supervision:C.L.P ., S.T ., andJ.-P .A. Writing—originaldraft: U.S.C.,S.T ., andJ.-P .A. Writing—reviewandediting:O.R.,A.R.B.,C.L.P ., S.T ., andJ.-P .A. Competinginterests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataand materialsavailability:Alldataneededtoevaluatetheconclusionsinthepaperarepresentin thepaperand/ortheSupplementaryMaterials.TheatomiccoordinatesoftheSIRT6-nucleosomecomplexhav ebeendepositedtotheRCSBPDBwithPDBID8G57.Thecryo-EM Coulombpotentialmapforthebest-resolvedSIRT6-nucleosomecomplexwasdepositedinthe ElectronMicroscopyDataBankasEMD-29735.Therawcryo-EMdataweredepositedinEMPIAR (EMPIAR-11427). Funding Information: This work was supported by National Institutes of Health (NIH) grant F32GM137463 (U.S.C.), NIH grant T32BM107000 (A.R.B.), NIH grant R35GM122519 (C.L.P.), and NIH grant R35GM127034 (S.T.). Research reported in this publication was supported by the Office of the Director, NIH, under award number S10OD026822-01. This project is funded, in part, under a grant from the Pennsylvania Department of Health using Tobacco CURE Funds. The Department specifically disclaims responsibility for any analyses, interpretations or conclusion. This research was, in part, supported by the National Cancer Institute{\textquoteright}s National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research under contract HSSN261200800001E. A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL, a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. The figures for this manuscript were generated using PyMOL and UCSF ChimeraX. UCSF ChimeraX is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",
year = "2023",
month = apr,
doi = "10.1126/sciadv.adf7586",
language = "English (US)",
volume = "9",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "15",
}
