Inhibition of MRN activity by a telomere protein motif.pdf (3.33 MB)
Inhibition of MRN activity by a telomere protein motif
journal contribution
posted on 2023-06-10, 00:42 authored by Freddy KhayatFreddy Khayat, Elda Cannavo, Majedh AlshmeryMajedh Alshmery, William R Foster, Charly Chahwan, Martino Maddalena, Christophe Smith, Antony OliverAntony Oliver, Adam WatsonAdam Watson, Antony CarrAntony Carr, Petr Cejka, Alessandro BianchiAlessandro BianchiThe MRN complex (MRX in Saccharomyces cerevisiae, made of Mre11, Rad50 and Nbs1/Xrs2) initiates double-stranded DNA break repair and activates the Tel1/ATM kinase in the DNA damage response. Telomeres counter both outcomes at chromosome ends, partly by keeping MRN-ATM in check. We show that MRX is disabled by telomeric protein Rif2 through an N-terminal motif (MIN, MRN/X-inhibitory motif). MIN executes suppression of Tel1, DNA end-resection and non-homologous end joining by binding the Rad50 N-terminal region. Our data suggest that MIN promotes a transition within MRX that is not conductive for endonuclease activity, DNA-end tethering or Tel1 kinase activation, highlighting an Achilles’ heel in MRN, which we propose is also exploited by the RIF2 paralog ORC4 (Origin Recognition Complex 4) in Kluyveromyces lactis and the Schizosaccharomyces pombe telomeric factor Taz1, which is evolutionarily unrelated to Orc4/Rif2. This raises the possibility that analogous mechanisms might be deployed in other eukaryotes as well.
History
Publication status
- Published
File Version
- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Nature ResearchExternal DOI
Issue
1Volume
12Page range
1-16Article number
a3856Event location
EnglandDepartment affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-08-23First Open Access (FOA) Date
2021-08-23First Compliant Deposit (FCD) Date
2021-08-23Usage metrics
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No categories selectedKeywords
Amino Acid MotifsAmino Acid SequenceDNA BreaksDouble-StrandedDNA End-Joining RepairDNA HelicasesDNAFungalEndodeoxyribonucleasesExodeoxyribonucleasesGenomic InstabilityIntracellular Signaling Peptides and ProteinsOrigin Recognition ComplexProtein-Serine-Threonine KinasesSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSequence HomologyAmino AcidTelomereTelomere-Binding Proteins
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