title: Cyclin B-dependent kinase 1 regulates human TRF1 to modulate the resolution of sister telomeres.
abstract: Cyclin B-Cdk1 is a key mediator of mitotic entry; however, little is known about its role in the separation of sister chromatids. Here we report that upon mitotic entry, Cdk1 specifically phosphorylates threonine 371 of TRF1, a telomere binding protein implicated in the regulation of sister telomere cohesion. Such phosphorylation is removed in late mitosis when Cdk1 activity is inhibited, indicative of a tight regulation of T371 phosphorylation. We show that T371 phosphorylation by Cdk1 keeps TRF1 free of chromatin and this phosphorylation is associated with loss of telomere-bound TRF1 and TIN2, and a reduction in telomere heterochromatin. We find that a phosphomimic mutation at T371 of TRF1 induces telomere deprotection, resulting in telomere loss and the formation of telomere fusions, whereas a non-phosphorylatable substitution of T371 blocks sister telomere resolution, promotes micronuclei formation and impairs cell proliferation. Our work suggests that Cdk1 controls TRF1 association with telomeres to facilitate temporal telomere de-protection, which is essential for sister telomere resolution.
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Megan
authors.initials: M
authors.lastname: McKerlie
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Zhu
mesh_terms: D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002478:Cells, Cultured; D002842:Chromatids / Q000235:genetics / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D019926:Cyclin B / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D016615:Telomere / Q000235:genetics / Q000502:physiology*; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism
chemical_list: D019926:Cyclin B; D035321:Telomeric Repeat Binding Protein 1; D013912:Threonine; D016203:CDC2 Protein Kinase