Ku and DNA-dependent Protein Kinase Dynamic Conformations and Assembly Regulate DNA Binding and the Initial Non-homologous End Joining Complex

Hammel, Michal; Yu, Yaping; Mahaney, Brandi L.; Cai, Brandon; Ye, Ruiqiong; Phipps, Barry M.; Rambo, Robert P.; Hura, Greg L.; Pelikan, Martin; So, Sairei; Abolfath, Ramin M.; Chen, David J.; Lees-Miller, Susan P.; Tainer, John A.

doi:10.1074/jbc.m109.065615

Title: Ku and DNA-dependent Protein Kinase Dynamic Conformations and Assembly Regulate DNA Binding and the Initial Non-homologous End Joining Complex

Journal Article · Thu Nov 05 00:00:00 EST 2009 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.m109.065615· OSTI ID:1625068

Hammel, Michal ^[1]; Yu, Yaping ^[2]; Mahaney, Brandi L. ^[2]; Cai, Brandon ^[2]; Ye, Ruiqiong ^[2]; Phipps, Barry M. ^[2]; Rambo, Robert P. ^[1]; Hura, Greg L. ^[1]; Pelikan, Martin ^[3]; So, Sairei ^[4]; Abolfath, Ramin M. ^[4]; Chen, David J. ^[4]; Lees-Miller, Susan P. ^[2]; Tainer, John A. ^[5]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division
Univ. of Alberta, Edmonton, AB (Canada). Southern Alberta Cancer Research Inst. Dept. of Biochemistry and Molecular Biology
Univ. of Missouri, St. Louis, MO (United States). Dept. of Mathematics and Computer Sciences
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Radiation Oncology. Division of Molecular Radiation Biology
The Scripps Research Inst., La Jolla, CA (United States). Skaggs Inst. of Chemical Biology. Dept. of Molecular Biology; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division. Dept. of Molecular Biology

DNA double strand break (DSB) repair by non-homologous end joining (NHEJ) is initiated by DSB detection by Ku70/80 (Ku) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) recruitment, which promotes pathway progression through poorly defined mechanisms. Here, Ku and DNA-PKcs solution structures alone and in complex with DNA, defined by x-ray scattering, reveal major structural reorganizations that choreograph NHEJ initiation. The Ku80 C-terminal region forms a flexible arm that extends from the DNA-binding core to recruit and retain DNA-PKcs at DSBs. Furthermore, Ku- and DNA-promoted assembly of a DNA-PKcs dimer facilitates transautophosphorylation at the DSB. The resulting site-specific autophosphorylationinduces a large conformational change that opens DNA-PKcs and promote sits release from DNA ends. These results show how protein and DNA interactions initiate large Ku and DNA-PKcs rearrangements to control DNA-PK biological functions as a macromolecular machine orchestrating assembly and disassembly of the initial NHEJ complex on DNA.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1625068

Journal Information:: Journal of Biological Chemistry, Vol. 285, Issue 2; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells Khan, Atif J.; Misenko, Sarah M.; Thandoni, Aditya Oncotarget, Vol. 9, Issue 40 https://doi.org/10.18632/oncotarget.25383	journal	May 2018
Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway Su, Fengtao; Bhattacharya, Souparno; Abdisalaam, Salim Oncotarget, Vol. 7, Issue 1 https://doi.org/10.18632/oncotarget.6659	journal	December 2015
CoincidentIn VitroAnalysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining Hendrickson, Cynthia L.; Purkayastha, Shubhadeep; Pastwa, Elzbieta Journal of Nucleic Acids, Vol. 2010 https://doi.org/10.4061/2010/823917	journal	January 2010
Cell Cycle and DNA Damage Response in Postmitotic Neurons Kruman, Inna I. DNA Repair https://doi.org/10.5772/20859	book	November 2011

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