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The Ku-binding motif is a conserved module for recruitment and stimulation of non-homologous end-joining proteins
journal contribution
posted on 2023-06-09, 00:59 authored by Gabrielle J Grundy, Stuart L Rulten, Raquel Arribas, Kathryn Davidson, Zuzanna Kozik, Antony OliverAntony Oliver, Laurence PearlLaurence Pearl, Keith CaldecottKeith CaldecottThe Ku-binding motif (KBM) is a short peptide module first identified in APLF that we now show is also present in Werner syndrome protein (WRN) and in Modulator of retrovirus infection homologue (MRI). We also identify a related but functionally distinct motif in XLF, WRN, MRI and PAXX, which we denote the XLF-like motif. We show that WRN possesses two KBMs; one at the N terminus next to the exonuclease domain and one at the C terminus next to an XLF-like motif. We reveal that the WRN C-terminal KBM and XLF-like motif function cooperatively to bind Ku complexes and that the N-terminal KBM mediates Ku-dependent stimulation of WRN exonuclease activity. We also show that WRN accelerates DSB repair by a mechanism requiring both KBMs, demonstrating the importance of WRN interaction with Ku. These data define a conserved family of KBMs that function as molecular tethers to recruit and/or stimulate enzymes during NHEJ.
Funding
Non-homologous End-Joining Protein Complexes and Genome Stability; G1305; CANCER RESEARCH UK; C6563/A16771
Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug Discov; G0891; CANCER RESEARCH UK; C302/A14532
History
Publication status
- Published
File Version
- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Nature Publishing GroupExternal DOI
Issue
1Volume
7Article number
a11242Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-04-20First Open Access (FOA) Date
2016-04-20First Compliant Deposit (FCD) Date
2016-04-20Usage metrics
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