Fig. 7: The iDDR of TRF2 is predicted to compete with CtIP for binding to RAD50.

a, Predicted aligned error (PAE) plot from AlphaFold-Multimer modeling of human RAD50–TRF2. Representative of five ranked models generated with default parameters. b, pLDDT plot showing per-residue confidence score across human TRF2 from the ranked RAD50–TRF2 models. c, Predicted structure of a human RAD50 dimer with a dimer of human TRF2. The RAD50 coiled-coils were truncated for the dimer model. Only the iDDR of TRF2 is shown. d, PAE plot from the AlphaFold-Multimer modeling of human RAD50–CtIP. Representative of five ranked models generated with default parameters. e, pLDDT plot showing per-residue confidence score across human CtIP from the ranked RAD50–CtIP models. f, Predicted structure of a human RAD50 dimer with the Sae2-like domain of human CtIP. The RAD50–CtIP monomer model was superimposed on the predicted structure of an RAD50 dimer from c. g, Model for inhibition of MRN endonuclease activity by the TRF2 iDDR. TRF2 competes with CtIP for binding to RAD50, which stimulates the endonuclease-active state of MRN. h, Model for leading-end telomere processing and protection mediated by TRF2 and DNA-PK. TRF2 promotes the 5′-resection of the leading-end telomere by recruiting Apollo. In the absence of Apollo, either owing to Apollo deletion or the lack of recruitment due to TRF2-F120A, the newly replicated leading-end telomere ends cannot be resected and undergo fusion mediated by alt-NHEJ. In the absence of Apollo and the iDDR domain of TRF2, MRN–CtIP initiates resection at DNA-PK-bound leading-end telomeres, leading to telomere protection and the absence of fusions. When both DNA-PK and Apollo are absent, MRN can promote the resection of the free DNA ends, even in the presence of the TRF2 iDDR domain. See also Extended Data Figs. 5–7.