Inhibition of MRN activity by a telomere protein motif

Freddy Khayat, Elda Cannavo, Majedh Alshmery, William R. Foster, Charly Chahwan, Martino Maddalena, Christopher Smith, Antony W. Oliver, Adam T. Watson, Antony M. Carr, Petr Cejka and Alessandro Bianchi ()
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Freddy Khayat: University of Sussex
Elda Cannavo: Università della Svizzera italiana (USI)
Majedh Alshmery: University of Sussex
William R. Foster: University of Sussex
Charly Chahwan: University of Sussex
Martino Maddalena: University of Sussex
Christopher Smith: University of Sussex
Antony W. Oliver: University of Sussex
Adam T. Watson: University of Sussex
Antony M. Carr: University of Sussex
Petr Cejka: Università della Svizzera italiana (USI)
Alessandro Bianchi: University of Sussex

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract The 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.

Date: 2021
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DOI: 10.1038/s41467-021-24047-2

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