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Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres

Khayat, Freddy, Alshmery, Majedh, Pal, Mohinder, Oliver, Antony W., Bianchi, Alessandro (2024) Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres. Nucleic Acids Research, 52 (13). pp. 7704-7719. ISSN 0305-1048. E-ISSN 1362-4962. (doi:10.1093/nar/gkae509) (KAR id:106348)

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Official URL:
https://doi.org/10.1093/nar/gkae509

Abstract

Telomeres protect chromosome ends from unscheduled DNA repair, including from the MRN (MRE11, RAD50, NBS1) complex, which processes double-stranded DNA breaks (DSBs) via activation of the ATM kinase, promotes DNA end-tethering aiding the non-homologous end-joining (NHEJ) pathway, and initiates DSB resection through the MRE11 nuclease. A protein motif (MIN, for MRN inhibitor) inhibits MRN at budding yeast telomeres by binding to RAD50 and evolved at least twice, in unrelated telomeric proteins Rif2 and Taz1. We identify the iDDR motif of human shelterin protein TRF2 as a third example of convergent evolution for this telomeric mechanism for binding MRN, despite the iDDR lacking sequence homology to the MIN motif. CtIP is required for activation of MRE11 nuclease action, and we provide evidence for binding of a short C-terminal region of CtIP to a RAD50 interface that partly overlaps with the iDDR binding site, indicating that the interaction is mutually exclusive. In addition, we show that the iDDR impairs the DNA binding activity of RAD50. These results highlight direct inhibition of MRN action as a crucial role of telomeric proteins across organisms and point to multiple mechanisms enforced by the iDDR to disable the many activities of the MRN complex.

Item Type: Article
DOI/Identification number: 10.1093/nar/gkae509
Uncontrolled keywords: DNA
Subjects: Q Science
Q Science > QH Natural history
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: Cancer Research UK (https://ror.org/054225q67)
University of Sussex (https://ror.org/00ayhx656)
Depositing User: Mohinder Pal
Date Deposited: 20 Jun 2024 10:14 UTC
Last Modified: 05 Nov 2024 13:12 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/106348 (The current URI for this page, for reference purposes)

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