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冷冻电镜解析 NHEJ 超复合物有助于深入了解 DNA 修复。

Cryo-EM of NHEJ supercomplexes provides insights into DNA repair.

机构信息

Department of Biochemistry, University of Cambridge, Sanger Building, Tennis Court Road, Cambridge CB2 1GA, UK.

CryoEM Facility, Department of Biochemistry, University of Cambridge, Sanger Building, Tennis Court Road, Cambridge CB2 1GA, UK.

出版信息

Mol Cell. 2021 Aug 19;81(16):3400-3409.e3. doi: 10.1016/j.molcel.2021.07.005. Epub 2021 Aug 4.

DOI:10.1016/j.molcel.2021.07.005
PMID:34352203
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9006396/
Abstract

Non-homologous end joining (NHEJ) is one of two critical mechanisms utilized in humans to repair DNA double-strand breaks (DSBs). Unrepaired or incorrect repair of DSBs can lead to apoptosis or cancer. NHEJ involves several proteins, including the Ku70/80 heterodimer, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), X-ray cross-complementing protein 4 (XRCC4), XRCC4-like factor (XLF), and ligase IV. These core proteins bind DSBs and ligate the damaged DNA ends. However, details of the structural assembly of these proteins remain unclear. Here, we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA, revealing the detailed structural architecture of this assembly. We describe monomeric and dimeric forms of this supercomplex and also propose the existence of alternate dimeric forms of long-range synaptic complexes. Finally, we show that mutational disruption of several structural features within these NHEJ complexes negatively affects DNA repair.

摘要

非同源末端连接（NHEJ）是人类用于修复 DNA 双链断裂（DSB）的两种关键机制之一。DSB 未修复或修复不正确会导致细胞凋亡或癌症。NHEJ 涉及几种蛋白质，包括 Ku70/80 异二聚体、DNA 依赖性蛋白激酶催化亚基（DNA-PKcs）、X 射线修复交叉互补蛋白 4（XRCC4）、XRCC4 样因子（XLF）和连接酶 IV。这些核心蛋白结合 DSB 并连接受损的 DNA 末端。然而，这些蛋白质的结构组装细节尚不清楚。在这里，我们展示了由这些核心蛋白和 DNA 组成的 NHEJ 超复合体的冷冻电镜结构，揭示了该组装的详细结构架构。我们描述了这种超复合体的单体和二聚体形式，并提出了长程突触复合物的交替二聚体形式的存在。最后，我们表明，这些 NHEJ 复合物中几个结构特征的突变破坏会对 DNA 修复产生负面影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/f693358279b0/nihms-1790590-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/ef882b666365/nihms-1790590-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/c2a66df16856/nihms-1790590-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/3061ff406131/nihms-1790590-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/518b9f5b72e7/nihms-1790590-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/bf09de45ae62/nihms-1790590-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/f693358279b0/nihms-1790590-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/ef882b666365/nihms-1790590-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/c2a66df16856/nihms-1790590-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/3061ff406131/nihms-1790590-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/518b9f5b72e7/nihms-1790590-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/bf09de45ae62/nihms-1790590-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f1/9006396/f693358279b0/nihms-1790590-f0007.jpg

相似文献

[1]
Cryo-EM of NHEJ supercomplexes provides insights into DNA repair.

Mol Cell. 2021-8-19

[2]
Structural basis of long-range to short-range synaptic transition in NHEJ.

Nature. 2021-5

[3]
Genetic interaction between DNA repair factors PAXX, XLF, XRCC4 and DNA-PKcs in human cells.

FEBS Open Bio. 2019-6-12

[4]
An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex.

J Biol Chem. 2016-12-30

[5]
X-ray scattering reveals disordered linkers and dynamic interfaces in complexes and mechanisms for DNA double-strand break repair impacting cell and cancer biology.

Protein Sci. 2021-9

[6]
Cryo-EM structure of a DNA-PK trimer: higher order oligomerisation in NHEJ.

Structure. 2023-8-3

[7]
Non-Homologous End Joining Factors XLF, PAXX and DNA-PKcs Maintain the Neural Stem and Progenitor Cell Population.

Biomolecules. 2020-12-28

[8]
Two-Stage Synapsis of DNA Ends during Non-homologous End Joining.

Mol Cell. 2016-3-17

[9]
Synthetic lethality between murine DNA repair factors XLF and DNA-PKcs is rescued by inactivation of Ku70.

DNA Repair (Amst). 2017-9

[10]
DNA-dependent protein kinase and XRCC4-DNA ligase IV mobilization in the cell in response to DNA double strand breaks.

J Biol Chem. 2005-2-25

引用本文的文献

[1]
Restriction of Ku translocation protects telomere ends.

Nat Commun. 2025-7-24

[2]
53BP1/RIF1 and DNA-PKcs show distinct genetic interactions with diverse chromosomal break repair outcomes.

bioRxiv. 2025-5-11

[3]
Distinct functions of PAXX and MRI during chromosomal end joining.

iScience. 2025-5-22

[4]
Structural and functional insights into the interaction between Ku70/80 and Pol X family polymerases in NHEJ.

Nat Commun. 2025-5-6

[5]
Utilization of natural products in diverse pathogeneses of diseases associated with single or double DNA strand damage repair.

Chin Med. 2025-4-7

[6]
Lig3-dependent rescue of mouse viability and DNA double-strand break repair by catalytically inactive Lig4.

Nucleic Acids Res. 2025-1-11

[7]
Impact of Optimized Ku-DNA Binding Inhibitors on the Cellular and In Vivo DNA Damage Response.

Cancers (Basel). 2024-9-26

[8]
Distinct functions of PAXX and MRI during chromosomal end joining.

bioRxiv. 2024-8-22

[9]
Compared to other NHEJ factors, DNA-PK protein and RNA levels are markedly increased in all higher primates, but not in prosimians or other mammals.

DNA Repair (Amst). 2024-10

[10]
DNA-PK: A synopsis beyond synapsis.

DNA Repair (Amst). 2024-9

本文引用的文献

[1]
Structural basis of long-range to short-range synaptic transition in NHEJ.

Nature. 2021-5

[2]
3D variability analysis: Resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM.

J Struct Biol. 2021-6

[3]
The active DNA-PK holoenzyme occupies a tensed state in a staggered synaptic complex.

Structure. 2021-5-6

[4]
Structure of an activated DNA-PK and its implications for NHEJ.

Mol Cell. 2021-2-18

[5]
XLF acts as a flexible connector during non-homologous end joining.

Elife. 2020-12-8

[6]
Dimers of DNA-PK create a stage for DNA double-strand break repair.

Nat Struct Mol Biol. 2021-1

[7]
Activation of DNA-PK by hairpinned DNA ends reveals a stepwise mechanism of kinase activation.

Nucleic Acids Res. 2020-9-18

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Nat Methods. 2019-10-7

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IUCrJ. 2019-6-27

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XLF and APLF bind Ku80 at two remote sites to ensure DNA repair by non-homologous end joining.

Nat Struct Mol Biol. 2018-10-5

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