Cyclin B-dependent kinase 1 regulates human TRF1 to modulate the resolution of sister telomeres

• DOI: 10.1038/ncomms1372
• Publication Date: 2011-06-28T09:33:03Z
• Authors: Megan McKerlie; Xu-Dong Zhu
• Keywords: Threonine; 0301 basic medicine; Chromatin Immunoprecipitation; 0303 health sciences; Electrophoretic Mobility Shift Assay; Chromatids; Cyclin B; Telomere; Article; 03 medical and health sciences; Microscopy, Fluorescence; CDC2 Protein Kinase; In Situ Nick-End Labeling; Mutagenesis, Site-Directed; Humans; Telomeric Repeat Binding Protein 1; Phosphorylation; Cells, Cultured; In Situ Hybridization, Fluorescence

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.