Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation.
Telomere maintenance is essential for continued cell proliferation and chromosome stability. Telomeres are maintained by telomerase and a collection of associated proteins. The telomeric protein telomeric repeat binding factor 1 (TRF1) negatively regulates telomere length by inhibiting access of telomerase at telomere termini. Here we report that TRF1 interacts with the beta subunit of casein kinase 2 (CK2) and serves as a substrate for CK2. CK2-mediated phosphorylation is required for the efficient telomere binding of TRF1 in vitro and in vivo. Inhibition of CK2 by the CK2 inhibitor 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole decreased the ability of TRF1 to bind telomeric DNA. The resulting telomere-unbound form of TRF1 was then ubiquitinated and degraded by the proteasome. Partial knockdown of CK2 by small interfering RNA resulted in removal of TRF1 from telomeres and subsequent degradation of TRF1. Mapping of the CK2 target site identified threonine 122 as a substrate in TRF1. A threonine to alanine change at this position led to a diminished DNA binding due to reduced dimerization of TRF1. In addition, phosphorylation of threonine 122 seemed critical for TRF1-mediated telomere length control. Our findings suggest that CK2-mediated phosphorylation of TRF1 plays an important role in modulating telomere length homeostasis by determining the levels of TRF1 at telomeres.
Kim
Mi Kyung
MK
Department of Biology and Molecular Aging Research Center, Yonsei University, Seoul, Korea.
Kang
Mi Ran
MR
Nam
Hyung Wook
HW
Bae
Young-Seuk
YS
Kim
Yu Sam
YS
Chung
In Kwon
IK
D047390:Casein Kinase II / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D021241:Spectrometry, Mass, Electrospray Ionization; D016615:Telomere / Q000648:ultrastructure; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000737:chemistry
D004791:Enzyme Inhibitors; D035321:Telomeric Repeat Binding Protein 1; D025801:Ubiquitin; D013912:Threonine; D005982:Glutathione Transferase; D047390:Casein Kinase II