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DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres
Rockefeller Univ, NY 10021 USA.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0003-0451-1839
Univ Texas, TX USA.
Rockefeller Univ, NY 10021 USA.
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2023 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 30, no 9, p. 1346-+Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PORTFOLIO , 2023. Vol. 30, no 9, p. 1346-+
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-199141DOI: 10.1038/s41594-023-01072-xISI: 001085159500020PubMedID: 37653239OAI: oai:DiVA.org:liu-199141DiVA, id: diva2:1811776
Note

Funding Agencies|Cancerfonden [CAN 2018/493]; Vetenskapsradet [AR-MH 2018-03215]; NIH [R01GM138548, R35 CA210036, AG016642]; Knut and Alice Wallenberg Foundation; Lions forskningsfond [LiU-2022-01245]

Available from: 2023-11-14 Created: 2023-11-14 Last updated: 2023-11-14

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