| First Author | Myler LR | Year | 2023 |
| Journal | Nat Struct Mol Biol | Volume | 30 |
| Issue | 9 | Pages | 1346-1356 |
| PubMed ID | 37653239 | Mgi Jnum | J:340115 |
| Mgi Id | MGI:7524642 | Doi | 10.1038/s41594-023-01072-x |
| Citation | Myler LR, et al. (2023) DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres. Nat Struct Mol Biol |
| abstractText | 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. |
