Structure and mechanism in non-homologous end joining.
Cryo-EM
Double-strand break repair
NHEJ
Structural biology
Journal
DNA repair
ISSN: 1568-7856
Titre abrégé: DNA Repair (Amst)
Pays: Netherlands
ID NLM: 101139138
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
02
06
2023
revised:
26
07
2023
accepted:
27
07
2023
pmc-release:
01
10
2024
medline:
25
9
2023
pubmed:
10
8
2023
entrez:
9
8
2023
Statut:
ppublish
Résumé
DNA double-stranded breaks (DSBs) are a particularly challenging form of DNA damage to repair because the damaged DNA must not only undergo the chemical reactions responsible for returning it to its original state, but, additionally, the two free ends can become physically separated in the nucleus and must be bridged prior to repair. In nonhomologous end joining (NHEJ), one of the major pathways of DSB repair, repair is carried out by a number of repair factors capable of binding to and directly joining DNA ends. It has been unclear how these processes are carried out at a molecular level, owing in part to the lack of structural evidence describing the coordination of the NHEJ factors with each other and a DNA substrate. Advances in cryo-Electron Microscopy (cryo-EM), allowing for the structural characterization of large protein complexes that would be intractable using other techniques, have led to the visualization several key steps of the NHEJ process, which support a model of sequential assembly of repair factors at the DSB, followed by end-bridging mediated by protein-protein complexes and transition to full synapsis. Here we examine the structural evidence for these models, devoting particular attention to recent work identifying a new NHEJ intermediate state and incorporating new NHEJ factors into the general mechanism. We also discuss the evolving understanding of end-bridging mechanisms in NHEJ and DNA-PKcs's role in mediating DSB repair.
Identifiants
pubmed: 37556875
pii: S1568-7864(23)00101-5
doi: 10.1016/j.dnarep.2023.103547
pmc: PMC10528545
mid: NIHMS1924231
pii:
doi:
Substances chimiques
DNA
9007-49-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
103547Subventions
Organisme : NCI NIH HHS
ID : P01 CA092584
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM135651
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM144559
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008382
Pays : United States
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that there are no conflicts of interest.
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