期刊
NATURE
卷 593, 期 7858, 页码 294-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03458-7
关键词
-
资金
- Cornew Innovation Award from the Chemistry of Life Processes Institute at Northwestern University
- Catalyst Award by the Chicago Biomedical Consortium
- Searle Funds at The Chicago Community Trust
- Institutional Research Grant from the American Cancer Society [IRG-15-173-21]
- H Foundation Core Facility Pilot Project Award
- Pilot Project Award [U54CA193419]
- NIH [R01 GM135651, U24GM129547, 1S10OD026963-01, R01GM047251]
- Molecular Biophysics Training Program from NIGMS/NIH [5T32 GM008382]
- Office of Biological and Environmental Research [grid.436923.9]
- NCI CCSG [P30 CA060553, P30 CA118100]
- Chicago Biomedical Consortium
- Canadian Institutes of Health [16939]
- Engineered Air Chair in Cancer Research
- University of New Mexico Comprehensive Cancer Center
- NCI [P01 CA092584]
In this study, single-particle cryo-electron microscopy was used to visualize two key DNA-protein complexes formed by human NHEJ factors, revealing their structure and interactions.
DNA double-strand breaks (DSBs) are a highly cytotoxic form of DNA damage and the incorrect repair of DSBs is linked to carcinogenesis(1,2). 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 receptors(2,3). 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 angstrom 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据