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Two distinct long-range synaptic complexes promote different aspects of end processing prior to repair of DNA breaks by non-homologous end joining

journal contribution
posted on 2023-11-02, 16:11 authored by CJ Buehl, NJ Goff, SW Hardwick, M Gellert, TL Blundell, W Yang, AK Chaplin, K Meek

Non-homologous end joining is the major double-strand break repair (DSBR) pathway in mammals. DNA-PK is the hub and organizer of multiple steps in non-homologous end joining (NHEJ). Recent high-resolution structures show how two distinct NHEJ complexes “synapse” two DNA ends. One complex includes a DNA-PK dimer mediated by XLF, whereas a distinct DNA-PK dimer forms via a domain-swap mechanism where the C terminus of Ku80 from one DNA-PK protomer interacts with another DNA-PK protomer in trans. Remarkably, the distance between the two synapsed DNA ends in both dimers is the same (∼115 Å), which matches the distance observed in the initial description of an NHEJ long-range synaptic complex. Here, a mutational strategy is used to demonstrate distinct cellular function(s) of the two dimers: one promoting fill-in end processing, while the other promotes DNA end resection. Thus, the specific DNA-PK dimer formed (which may be impacted by DNA end structure) dictates the mechanism by which ends will be made ligatable.

History

Author affiliation

Leicester Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester

Version

  • VoR (Version of Record)

Published in

Molecular Cell

Volume

83

Issue

5

Pagination

698 - 714.e4

Publisher

Elsevier BV

issn

1097-2765

eissn

1097-4164

Copyright date

2023

Spatial coverage

United States

Language

eng

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