DNA-PK controls Apollo's access to leading-end telomeres.
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Date
2024-05-08ICR Author
Author
Sonmez, C
Toia, B
Eickhoff, P
Matei, AM
El Beyrouthy, M
Wallner, B
Douglas, ME
de Lange, T
Lottersberger, F
Type
Journal Article
Metadata
Show full item recordAbstract
The complex formed by Ku70/80 and DNA-PKcs (DNA-PK) promotes the synapsis and the joining of double strand breaks (DSBs) during canonical non-homologous end joining (c-NHEJ). In c-NHEJ during V(D)J recombination, DNA-PK promotes the processing of the ends and the opening of the DNA hairpins by recruiting and/or activating the nuclease Artemis/DCLRE1C/SNM1C. Paradoxically, DNA-PK is also required to prevent the fusions of newly replicated leading-end telomeres. Here, we describe the role for DNA-PK in controlling Apollo/DCLRE1B/SNM1B, the nuclease that resects leading-end telomeres. We show that the telomeric function of Apollo requires DNA-PKcs's kinase activity and the binding of Apollo to DNA-PK. Furthermore, AlphaFold-Multimer predicts that Apollo's nuclease domain has extensive additional interactions with DNA-PKcs, and comparison to the cryo-EM structure of Artemis bound to DNA-PK phosphorylated on the ABCDE/Thr2609 cluster suggests that DNA-PK can similarly grant Apollo access to the DNA end. In agreement, the telomeric function of DNA-PK requires the ABCDE/Thr2609 cluster. These data reveal that resection of leading-end telomeres is regulated by DNA-PK through its binding to Apollo and its (auto)phosphorylation-dependent positioning of Apollo at the DNA end, analogous but not identical to DNA-PK dependent regulation of Artemis at hairpins.
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Subject
DNA-Activated Protein Kinase
Telomere
Humans
DNA-Binding Proteins
Endonucleases
DNA End-Joining Repair
Nuclear Proteins
Ku Autoantigen
Protein Binding
DNA Breaks, Double-Stranded
Phosphorylation
DNA
Research team
Telomere Biology
Language
eng
Date accepted
2024-02-01
License start date
2024-05-08
Citation
Nucleic Acids Research (NAR), 2024, 52 (8), pp. 4313 - 4327
Publisher
OXFORD UNIV PRESS