TRF1 averts chromatin remodelling, recombination and replication dependent-break induced replication at mouse telomeres
Rosa Maria Porreca,
Emilia Herrera-Moyano,
Eleni Skourti,
Pui Pik Law,
Roser Gonzalez Franco,
Alex Montoya,
Peter Faull,
Holger Kramer,
Jean-Baptiste Vannier
Affiliations
Rosa Maria Porreca
Telomere Replication and Stability group, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Emilia Herrera-Moyano
Telomere Replication and Stability group, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Eleni Skourti
Telomere Replication and Stability group, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Telomere Replication and Stability group, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Roser Gonzalez Franco
Telomere Replication and Stability group, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Alex Montoya
Biological Mass Spectrometry and Proteomics, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom
Biological Mass Spectrometry and Proteomics, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom; The Francis Crick Institute, Proteomics Mass Spectrometry Science and Technology Platform, London, United Kingdom
Holger Kramer
Biological Mass Spectrometry and Proteomics, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom
Telomere Replication and Stability group, Medical Research Council - London Institute of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
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.
