PMID:22266654

Citation	McKerlie, M, Lin, S and Zhu, XD (2012) ATM regulates proteasome-dependent subnuclear localization of TRF1, which is important for telomere maintenance. Nucleic Acids Res. 40:3975-89
Abstract	Ataxia telangiectasia mutated (ATM), a PI-3 kinase essential for maintaining genomic stability, has been shown to regulate TRF1, a negative mediator of telomerase-dependent telomere extension. However, little is known about ATM-mediated TRF1 phosphorylation site(s) in vivo. Here, we report that ATM phosphorylates S367 of TRF1 and that this phosphorylation renders TRF1 free of chromatin. We show that phosphorylated (pS367)TRF1 forms distinct non-telomeric subnuclear foci and that these foci occur predominantly in S and G2 phases, implying that their formation is cell cycle regulated. We show that phosphorylated (pS367)TRF1-containing foci are sensitive to proteasome inhibition. We find that a phosphomimic mutation of S367D abrogates TRF1 binding to telomeric DNA and renders TRF1 susceptible to protein degradation. In addition, we demonstrate that overexpressed TRF1-S367D accumulates in the subnuclear domains containing phosphorylated (pS367)TRF1 and that these subnuclear domains overlap with nuclear proteasome centers. Taken together, these results suggest that phosphorylated (pS367)TRF1-containing foci may represent nuclear sites for TRF1 proteolysis. Furthermore, we show that TRF1 carrying the S367D mutation is unable to inhibit telomerase-dependent telomere lengthening or to suppress the formation of telomere doublets and telomere loss in TRF1-depleted cells, suggesting that S367 phosphorylation by ATM is important for the regulation of telomere length and stability.
Links	PubMed PMC3351164 Online version:10.1093/nar/gks035
Keywords	Cell Cycle; Cell Cycle Proteins/metabolism; Cell Line; Cell Nucleus/chemistry; Cell Nucleus/enzymology; Cell Nucleus/metabolism; DNA-Binding Proteins/metabolism; Humans; Mutation; Phosphorylation; Proteasome Endopeptidase Complex/antagonists & inhibitors; Proteasome Endopeptidase Complex/metabolism; Protein-Serine-Threonine Kinases/metabolism; Telomerase/metabolism; Telomere/chemistry; Telomere Homeostasis; Telomeric Repeat Binding Protein 1/analysis; Telomeric Repeat Binding Protein 1/genetics; Telomeric Repeat Binding Protein 1/metabolism; Tumor Suppressor Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ATM		GO:0004674: protein serine/threonine kinase activity	ECO:0000314:		F		ATM phosphorylates TRF1 at serine367: Figure 1.	complete
BOVIN:A7E3R3		GO:0044454: nuclear chromosome part	ECO:0000315:		C		Figure 2 demonstrates how the TRF1 function on the chromosome is cell cycle regulated.	complete CACAO 3614

References

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