title: TopoIIα prevents telomere fragility and formation of ultra thin DNA bridges during mitosis through TRF1-dependent binding to telomeres.
abstract: Telomeres are repetitive nucleoprotein structures at the ends of chromosomes. Like most genomic regions consisting of repetitive DNA, telomeres are fragile sites prone to replication fork stalling and generation of chromosomal instability. In particular, abrogation of the TRF1 telomere binding protein leads to stalled replication forks and aberrant telomere structures known as "multitelomeric signals". Here, we report that TRF1 deficiency also leads to the formation of "ultra-fine bridges" (UFB) during mitosis, and to an increased time to complete mitosis mediated by the spindle assembly checkpoint proteins (SAC). We find that topoisomerase IIα (TopoIIα), an enzyme essential for resolution of DNA replication intermediates, binds telomeres in a TRF1-mediated manner. Indeed, similar to TRF1 abrogation, TopoIIα downregulation leads to telomere fragility and UFB, suggesting that these phenotypes are due to decreased TopoIIα at telomeres. We find that SAC proteins bind telomeres in vivo, and that this is disrupted upon TRF1 deletion. These findings suggest that TRF1 links TopoIIα and SAC proteins in a pathway that ensures correct telomere replication and mitotic segregation, unveiling how TRF1 protects from telomere fragility and mitotic defects.
authors.affiliation: Telomeres and Telomerase Group; Molecular Oncology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
authors.forename: Martina Stagno
authors.initials: MS
authors.lastname: d'Alcontres
authors.affiliation: Telomeres and Telomerase Group; Molecular Oncology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
authors.forename: Jose Alejandro
authors.initials: JA
authors.lastname: Palacios
authors.affiliation: Confocal Microscopy Unit; Biotechnology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Mejias
authors.affiliation: Telomeres and Telomerase Group; Molecular Oncology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C501384:MAD1L1 protein, human; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D035321:Telomeric Repeat Binding Protein 1; D004247:DNA; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases; D004250:DNA Topoisomerases, Type II
keywords: SAC; Shelterin; TRF1; TopoII; fragility; mitosis