title: Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX.
abstract: Fifteen per cent of cancers maintain telomere length independently of telomerase by the homologous recombination (HR)-associated alternative lengthening of telomeres (ALT) pathway. A unifying feature of these tumours are mutations in ATRX. Here we show that expression of ectopic ATRX triggers a suppression of the pathway and telomere shortening. Importantly ATRX-mediated ALT suppression is dependent on the histone chaperone DAXX. Re-expression of ATRX is associated with a reduction in replication fork stalling, a known trigger for HR and loss of MRN from telomeres. A G-quadruplex stabilizer partially reverses the effect of ATRX, inferring ATRX may normally facilitate replication through these sequences that, if they persist, promote ALT. We propose that defective telomere chromatinization through loss of ATRX promotes the persistence of aberrant DNA secondary structures, which in turn present a barrier to DNA replication, leading to replication fork stalling, collapse, HR and subsequent recombination-mediated telomere synthesis in ALT cancers.
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: David
authors.initials: D
authors.lastname: Clynes
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Jelinska
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Xella
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Ayyub
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Scott
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitson
authors.affiliation: Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Taylor
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gibbons
mesh_terms: D045744:Cell Line, Tumor; D002477:Cells; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism; D059505:Telomere Homeostasis / Q000502:physiology*; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein