Multi-step coordination of telomerase recruitment in fission yeast through two coupled telomere-telomerase interfaces

Tightly controlled recruitment of telomerase, a low-abundance enzyme, to telomeres is essential for regulated telomere synthesis. Recent studies in human cells revealed that a patch of amino acids in the shelterin component TPP1, called the TEL-patch, is essential for recruiting telomerase to telomeres. However, how TEL-patch—telomerase interaction integrates into the overall orchestration of telomerase regulation at telomeres is unclear. In fission yeast, Tel1ATM/Rad3ATR-mediated phosphorylation of shelterin component Ccq1 during late S phase is involved in telomerase recruitment through promoting the binding of Ccq1 to a telomerase accessory protein Est1. Here, we identify the TEL-patch in Tpz1TPP1, mutations of which lead to decreased telomeric association of telomerase, similar to the phosphorylation-defective Ccq1. Furthermore, we find that telomerase action at telomeres requires formation and resolution of an intermediate state, in which the cell cycle-dependent Ccq1-Est1 interaction is coupled to the TEL-patch—Trt1 interaction, to achieve temporally regulated telomerase elongation of telomeres.

GNL3L stabilizes the TRF1 complex and promotes mitotic transition

Telomeric repeat binding factor 1 (TRF1) is a component of the multiprotein complex “shelterin,” which organizes the telomere into a high-order structure. TRF1 knockout embryos suffer from severe growth defects without apparent telomere dysfunction, suggesting an obligatory role for TRF1 in cell cycle control. To date, the mechanism regulating the mitotic increase in TRF1 protein expression and its function in mitosis remains unclear. Here, we identify guanine nucleotide-binding protein-like 3 (GNL3L), a GTP-binding protein most similar to nucleostemin, as a novel TRF1-interacting protein in vivo. GNL3L binds TRF1 in the nucleoplasm and is capable of promoting the homodimerization and telomeric association of TRF1, preventing promyelocytic leukemia body recruitment of telomere-bound TRF1, and stabilizing TRF1 protein by inhibiting its ubiquitylation and binding to FBX4, an E3 ubiquitin ligase for TRF1. Most importantly, the TRF1 protein-stabilizing activity of GNL3L mediates the mitotic increase of TRF1 protein and promotes the metaphase-to-anaphase transition. This work reveals novel aspects of TRF1 modulation by GNL3L.

Giant Cell Tumor of Soft Tissue with Pulmonary Metastases: Pathologic and Cytogenetic Study

Giant cell tumor of soft tissue (GCTST) has gained general acceptance as an uncommon but distinct primary soft tissue tumor since it was first described in 1972. GCTST is predominantly seen in adults and typically shows uniformly dispersed osteoclast-like giant cells admixed with oval to polygonal mononuclear cells. It usually follows a benign clinical course, although the malignant variant has been described in cases in which the mononuclear cells demonstrate obvious dysplastic features. It is still not clear whether the two variants belong to the spectrum of the same tumor. No cytogenetic chromosomal abnormalities have been reported in the literature of GCTST. Interestingly, the osseous counterpart of giant cell tumor, which shares similar histologic features, quite often displays a telomeric association at the cytogenetic level, a finding that has never been reported in GCTST. We report the case of a 12-year-old girl with GCTST of the right leg that metastasized to the lung. Cytogenetic studies from the primary tumor showed the phenomenon of telomeric association involving multiple chromosomes.