All roads lead to MRN regulation at telomeres: different paths to one solution

Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres

“…Interestingly, the MIN motif of RIf2 has recently been proposed to disrupt Tel1 association with MRX and DSBs, not MRX association with DSBs ( 54 ). Our novel observation that the iDDR is capable of interfering with RAD50 DNA binding activity offers a rationale for interpreting the pleiotropic effects of the Rif2 MIN in yeast cells and opens the possibilities that these convergent MRN-disabling telomeric motifs might have multiple mechanisms of action in common ( 53 ). Further work will be required to fully elucidate the precise role of the iDDR and MIN motifs in the modulation of MRN activity at telomeres, but the analyses that we present here underscore how this is a ‘problem’ that has been addressed multiple times at telomeres during evolution, with a similar solution.…”

“…Because TRF2 interacts directly with NBS1 through its TRFH domain, in a manner regulated by NBS1 phosphorylation ( 50 ), and also with ATM ( 51 ), it has been unclear whether TRF2, or any other shelterin subunit, might act to regulate MRN at telomeres using a strategy similar to that employed by the MIN motif of yeast Rif2. Recent work has identified a role for the iDDR motif of TRF2 in controlling MRN-dependent resection at leading-end telomeres, in concert with DNA-PK, and in inhibiting the endonuclease action of MRN in vitro ( 52 ), proposing like us that these functions are carried out via binding to RAD50 ( 53 ). Here we address this question, showing that the iDDR motif of TRF2 binds to RAD50 in a manner similar to that of the MIN motif, and provide a comprehensive analysis and validation of the interaction model.…”