XRCC4 Protein Interactions with XRCC4-like Factor (XLF) Create an Extended Grooved Scaffold for DNA Ligation and Double Strand Break Repair

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dc.contributor.authorHammel, Michal
dc.contributor.authorRey, Martial
dc.contributor.authorYu, Yaping
dc.contributor.authorMani, Rajam S.
dc.contributor.authorClassen, Scott
dc.contributor.authorLiu, Mona
dc.contributor.authorPique, Michael E.
dc.contributor.authorFang, Shujuan
dc.contributor.authorMahaney, Brandi L.
dc.contributor.authorWeinfeld, Michael
dc.contributor.authorSchriemer, David C.
dc.contributor.authorLees-Miller, Susan P.
dc.contributor.authorTainer, John A.
dc.date.accessioned2017-09-07T23:23:01Z
dc.date.available2017-09-07T23:23:01Z
dc.date.issued2011-09-16
dc.description.abstractThe XRCC4-like factor (XLF)-XRCC4 complex is essential for nonhomologous end joining, the major repair pathway for DNA double strand breaks in human cells. Yet, how XLF binds XRCC4 and impacts nonhomologous end joining functions has been enigmatic. Here, we report the XLF-XRCC4 complex crystal structure in combination with biophysical and mutational analyses to define the XLF-XRCC4 interactions. Crystal and solution structures plus mutations characterize alternating XRCC4 and XLF head domain interfaces forming parallel super-helical filaments. XLF Leu-115 ("Leu-lock") inserts into a hydrophobic pocket formed by XRCC4 Met-59, Met-61, Lys-65, Lys-99, Phe-106, and Leu-108 in synergy with pseudo-symmetric β-zipper hydrogen bonds to drive specificity. XLF C terminus and DNA enhance parallel filament formation. Super-helical XLF-XRCC4 filaments form a positively charged channel to bind DNA and align ends for efficient ligation. Collective results reveal how human XLF and XRCC4 interact to bind DNA, suggest consequences of patient mutations, and support a unified molecular mechanism for XLF-XRCC4 stimulation of DNA ligation.en_US
dc.description.grantingagencyNational Institutes of Health; Canadian Institutes of Health Research; Alberta Cancer Foundationen_US
dc.description.refereedYesen_US
dc.description.sponsorshipThis work was supported, in whole or in part, by National Institutes of Health Grant P01 CA92584 (Structural Cell Biology of DNA Repair Machines) (to J. A. T. and S. P. L.-M.). This work was also supported by Grant 69139 from the Canadian Institutes of Health Research and Grant 23817 from Alberta Cancer Foundation (to S. P. L.-M. and M. W.).en_US
dc.identifier.citationHammel, M., Rey, M., Yu, Y., Mani, R. S., Classen, S., Liu, M., … Tainer, J. A. (2011). XRCC4 Protein Interactions with XRCC4-like Factor (XLF) Create an Extended Grooved Scaffold for DNA Ligation and Double Strand Break Repair. The Journal of Biological Chemistry, 286(37), 32638–32650. http://doi.org/10.1074/jbc.M111.272641en_US
dc.identifier.doi10.1074/jbc.M111.272641
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/33390
dc.identifier.grantnumberNIH Grant P01 CA92584; CIHR Grant 69139; ACF Grant 23817en_US
dc.identifier.urihttp://hdl.handle.net/1880/52208
dc.language.isoenen_US
dc.publisherJournal of Biological Chemistryen_US
dc.publisher.departmentPhysical Biosciences Divisionen_US
dc.publisher.institutionLawrence Berkeley National Laboratoryen_US
dc.publisher.urlhttp://www.jbc.org/en_US
dc.subjectDNA Repairen_US
dc.subjectProtein DNA-Interactionen_US
dc.subjectProtein Structureen_US
dc.subjectX-ray Crystallographyen_US
dc.subjectX-ray Scatteringen_US
dc.subjectDNA Ligase IVen_US
dc.subjectKuen_US
dc.subjectXLF-XRCC4 Complexen_US
dc.subjectNonhomologous End Joining (NHEJ)en_US
dc.subjectSmall Angle X-ray Scatteringen_US
dc.titleXRCC4 Protein Interactions with XRCC4-like Factor (XLF) Create an Extended Grooved Scaffold for DNA Ligation and Double Strand Break Repairen_US
dc.typejournal article
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