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

作者：Logan R. Myler, Beatrice Toia, Cara K. Vaughan, Kaori Takai, Andreea M. Matei, Peng Wu, Tanya T. Paull, Titia de Lange, Francisca Lottersberger · 发表于：Nature Structural & Molecular Biology · 年份：2023 · DOI：10.1038/s41594-023-01072-x · 被引用次数：40 · 研究领域：Telomeres, Telomerase, and Senescence、CRISPR and Genetic Engineering、DNA Repair Mechanisms

Telomeres 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.