Inhibition of MRN activity by a telomere protein motif

Khayat, Freddy, Cannavo, Elda, Alshmery, Majedh, Foster, William R, Chahwan, Charly, Maddalena, Martino, Smith, Christophe, Oliver, Antony W, Watson, Adam T, Carr, Antony M, Cejka, Petr and Bianchi, Alessandro (2021) Inhibition of MRN activity by a telomere protein motif. Nature Communications, 12 (1). a3856 1-16. ISSN 2041-1723

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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.

Item Type: Article
Keywords: Amino Acid Motifs, Amino Acid Sequence, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Helicases, DNA, Fungal, Endodeoxyribonucleases, Exodeoxyribonucleases, Genomic Instability, Intracellular Signaling Peptides and Proteins, Origin Recognition Complex, Protein-Serine-Threonine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Telomere, Telomere-Binding Proteins
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 23 Aug 2021 07:15
Last Modified: 23 Aug 2021 07:15
URI: http://sro.sussex.ac.uk/id/eprint/101256

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