Journal
FEBS JOURNAL
Volume 288, Issue 14, Pages 4382-4393Publisher
WILEY
DOI: 10.1111/febs.15732
Keywords
DNA double‐ strand break; integrative structural biology; Ku70; 80; nonhomologous end joining; SAP domain
Categories
Funding
- Wellcome Trust [200814/Z/16/Z, EM17057-43]
- Jack Brockhoff Foundation [JBF 4186]
- National Health, Medical Research Council (NHMRC) of Australia [GNT1174405]
- Victorian Government's Operational Infrastructure Support Program
- MRC [EM17057-43]
- BBSRC [EM17057-43]
- European Commission [731077]
- Centre of Molecular Structure Core Facility at BIOCEV [LM2018127]
- MEYS CR
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Nonhomologous end joining (NHEJ) is a DNA repair mechanism that maintains genomic integrity, with the Ku70/80 complex playing a critical role in recognizing DNA breaks. Research has shown that the SAP domain in the Ku70 C-terminal region changes its position depending on DNA binding, potentially serving as a flexible entry gate for broken DNA.
Nonhomologous end joining (NHEJ) is a DNA repair mechanism that religates double-strand DNA breaks to maintain genomic integrity during the entire cell cycle. The Ku70/80 complex recognizes DNA breaks and serves as an essential hub for recruitment of NHEJ components. Here, we describe intramolecular interactions of the Ku70 C-terminal domain, known as the SAP domain. Using single-particle cryo-electron microscopy, mass spectrometric analysis of intermolecular cross-linking and molecular modelling simulations, we captured variable positions of the SAP domain depending on DNA binding. The first position was localized at the DNA aperture in the Ku70/80 apo form but was not observed in the DNA-bound state. The second position, which was observed in both apo and DNA-bound states, was found below the DNA aperture, close to the helical arm of Ku70. The localization of the SAP domain in the DNA aperture suggests a function as a flexible entry gate for broken DNA. Databases EM maps have been deposited in EMDB (EMD-11933). Coordinates have been deposited in Protein Data Bank (PDB ). Other data are available from corresponding authors upon a request.
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