TRF1 averts chromatin remodelling, recombination and replication dependent-Break Induced Replication at mouse telomeres
Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that mouse telomeres lacking TRF1 undergo protein composition reorganisation associated with the recruitment of DNA damage response and chromatin remodellers. Surprisingly, mTRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for mTRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.Proteomic data have been made available at PRIDE, under the accession code PXD017022.
Article and author information
European Commission (637798 MetDNASecStr)
- Pui Pik Law
Medical Research Council (MRC Career Development Award)
- Emilia Herrera-Moyano
- Pui Pik Law
- Roser Gonzalez Franco
- Alex Montoya
- Holger Kramer
- Jean-Baptiste Vannier
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Raymund Wellinger, Université de Sherbrooke, Canada
- Received: July 1, 2019
- Accepted: January 11, 2020
- Accepted Manuscript published: January 14, 2020 (version 1)
- Version of Record published: January 28, 2020 (version 2)
- Version of Record updated: February 7, 2020 (version 3)
- Version of Record updated: February 10, 2020 (version 4)
© 2020, Porreca et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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