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.
Highlights
The MRN complex (MRX in Saccharomyces cerevisiae, made of Mre[11], Rad[50] and Nbs1/Xrs2) initiates double-stranded DNA break repair and activates the Tel1/ATM kinase in the DNA damage response
We suggest that MIN provides a powerful and comprehensive mechanism for telomeres to inactivate the multiple actions of MRN-Tel[1] at chromosome ends and that this mechanism has independently arisen in multiple lineages during fungal evolution
RIF2 evolved from the gene coding for the Origin Recognition Complex 4 subunit (ORC4) after a whole-genome duplication (WGD) event that occurred in budding yeast and related species[33,40]
Summary
The MRN complex (MRX in Saccharomyces cerevisiae, made of Mre[11], Rad[50] and Nbs1/Xrs2) initiates double-stranded DNA break repair and activates the Tel1/ATM kinase in the DNA damage response. Our data suggest that MIN promotes a transition within MRX that is not conductive for endonuclease activity, DNA-end tethering or Tel[1] kinase activation, highlighting an Achilles’ heel in MRN, which we propose is exploited by the RIF2 paralog ORC4 (Origin Recognition Complex 4) in Kluyveromyces lactis and the Schizosaccharomyces pombe telomeric factor Taz[1], which is evolutionarily unrelated to Orc4/Rif[2].
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