Dissemin is shutting down on January 1st, 2025

Published in

Nature Research, Nature Structural and Molecular Biology, 9(30), p. 1346-1356, 2023

DOI: 10.1038/s41594-023-01072-x

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DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Data provided by SHERPA/RoMEO

Abstract

AbstractTelomeres replicated by leading-strand synthesis lack the 3′ overhang required for telomere protection. Surprisingly, resection of these blunt telomeres is initiated by the telomere-specific 5′ exonuclease Apollo rather than the Mre11–Rad50–Nbs1 (MRN) complex, the nuclease that acts at DNA breaks. Without Apollo, leading-end telomeres undergo fusion, which, as demonstrated here, is mediated by alternative end joining. Here, we show that DNA-PK and TRF2 coordinate the repression of MRN at blunt mouse telomeres. DNA-PK represses an MRN-dependent long-range resection, while the endonuclease activity of MRN–CtIP, which could cleave DNA-PK off of blunt telomere ends, is inhibited in vitro and in vivo by the iDDR of TRF2. AlphaFold-Multimer predicts a conserved association of the iDDR with Rad50, potentially interfering with CtIP binding and MRN endonuclease activation. We propose that repression of MRN-mediated resection is a conserved aspect of telomere maintenance and represents an ancient feature of DNA-PK and the iDDR.