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

Data for paper published in <i>Nucleic Acids Research</i> (2024)Deposited data represent models generated by ColabFold in Protein Data Bank Format (.pdb). Software that can read molecular coordinate files in PDB format should allow visualisation of each model.Molecular Graphics Software:https://www.rcsb.org/docs/additional-resources/molecular-graphics-software<br><br><b>ColabFold / Alphafold2 models for telomeric proteins interacting with the head domain of Rad50</b>Telomeres protect chromosome ends from unscheduled DNA repair, including from the MRN (MRE11, RAD50, NBS1) complex, which processes double-stranded DNA breaks (DSBs) via activation of the ATM kinase, promotes DNA end-tethering aiding the non-homologous end-joining (NHEJ) pathway, and initiates DSB resection through the MRE11 nuclease. A protein motif (MIN, for MRN inhibitor) evolved at least twice in yeast, in unrelated telomeric proteins Rif2 and Taz1, and inhibits MRN at telomeres by binding to RAD50. We identify the iDDR motif of human shelterin protein TRF2 as a third example of convergent evolution for this binding mechanism for MRN at telomeres, despite the iDDR lacking sequence homology to the MIN motif. CtIP is required for activation of MRE11 nuclease action, and we provide evidence for binding of a short C-terminal region of CtIP to a RAD50 interface that partly overlaps with the iDDR binding site, indicating that the interaction is mutually exclusive. In addition, we show that the iDDR impairs the DNA binding activity of RAD50. These results highlight direct inhibition of MRN action as a crucial role of telomeric proteins across organisms and point to multiple mechanisms enforced by the iDDR to disable the many activities of the MRN complex.