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Structural basis of long-range to short-range synaptic transition in NHEJ.
Chen, Siyu; Lee, Linda; Naila, Tasmin; Fishbain, Susan; Wang, Annie; Tomkinson, Alan E; Lees-Miller, Susan P; He, Yuan.
Afiliación
  • Chen S; Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
  • Lee L; Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, USA.
  • Naila T; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
  • Fishbain S; Robson DNA Science Centre, Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
  • Wang A; Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
  • Tomkinson AE; Department of Molecular Genetics & Microbiology, University of New Mexico, Albuquerque, NM, USA.
  • Lees-Miller SP; University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.
  • He Y; Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
Nature ; 593(7858): 294-298, 2021 05.
Article en En | MEDLINE | ID: mdl-33854234
DNA double-strand breaks (DSBs) are a highly cytotoxic form of DNA damage and the incorrect repair of DSBs is linked to carcinogenesis1,2. The conserved error-prone non-homologous end joining (NHEJ) pathway has a key role in determining the effects of DSB-inducing agents that are used to treat cancer as well as the generation of the diversity in antibodies and T cell receptors2,3. Here we applied single-particle cryo-electron microscopy to visualize two key DNA-protein complexes that are formed by human NHEJ factors. The Ku70/80 heterodimer (Ku), the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), DNA ligase IV (LigIV), XRCC4 and XLF form a long-range synaptic complex, in which the DNA ends are held approximately 115 Å apart. Two DNA end-bound subcomplexes comprising Ku and DNA-PKcs are linked by interactions between the DNA-PKcs subunits and a scaffold comprising LigIV, XRCC4, XLF, XRCC4 and LigIV. The relative orientation of the DNA-PKcs molecules suggests a mechanism for autophosphorylation in trans, which leads to the dissociation of DNA-PKcs and the transition into the short-range synaptic complex. Within this complex, the Ku-bound DNA ends are aligned for processing and ligation by the XLF-anchored scaffold, and a single catalytic domain of LigIV is stably associated with a nick between the two Ku molecules, which suggests that the joining of both strands of a DSB involves both LigIV molecules.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: ADN / Microscopía por Crioelectrón / Roturas del ADN de Doble Cadena / Reparación del ADN por Unión de Extremidades Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: ADN / Microscopía por Crioelectrón / Roturas del ADN de Doble Cadena / Reparación del ADN por Unión de Extremidades Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos