Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres
Telomeres protect chromosome ends from unscheduled DNA repair, including from the MRN (MRE11, RAD50, NBS1) complex, which plays a critical role in the processing of double-stranded DNA breaks (DSBs). MRN orchestrates activation of the ATM kinase in the cellular DNA damage response (DDR), promotes DNA end-tethering aiding the nonhomologous end joining (NHEJ) pathway, and initiates DSB resection through the MRE11 nuclease. A previously identified protein motif (MIN, for MRN inhibitor) downregulates MRN activity via binding to RAD50 and has independently arisen at least twice, through convergent evolution of telomeric proteins Rif2 and Taz1, in budding and fission yeast respectively. We now provide a third example of convergent evolution for this binding mechanism for MRN at telomeres, by demonstrating that the iDDR motif of the human shelterin protein TRF2 binds to human RAD50 at the same site engaged by the MIN motif in the yeast proteins, despite lacking sequence homology. Modelling for the human CtIP interaction with RAD50 (necessary for activation of MRE11), and for the budding and fission yeast counterparts Sae2 and Ctp1, indicates that the interaction is mutually exclusive with binding of the iDDR/MIN motifs, pointing to a conserved mechanism for inhibition of MRN nuclease activity at telomeres.