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

Autor: Myler LR; Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY, USA., Toia B; Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden., Vaughan CK; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., Takai K; Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY, USA., Matei AM; Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden., Wu P; Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY, USA.; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Paull TT; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., de Lange T; Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY, USA. delange@mail.rockefeller.edu., Lottersberger F; Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden. francisca.lottersberger@liu.se.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2023 Sep; Vol. 30 (9), pp. 1346-1356. Date of Electronic Publication: 2023 Aug 31.
DOI: 10.1038/s41594-023-01072-x
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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