GNL3L stabilizes the TRF1 complex and promotes mitotic transition

Abstract

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.

Shelterin complex and associated factors at human telomeres

“…They are PIN1 and GNL3L, with GNL3L likely impeding FBX4 binding to TRF1. 73,74 PIN1 is a prolyl isomerase that binds and isomerizes target proteins at specific S/T-P motifs after phosphorylation. Indeed, TRF1 pull down by PIN1 is abrogated by phosphatase.…”

Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation

“…6 More recently, GNL3L has been identified as one among the factors that are responsible for the maintenance of tumorigenic property of tumor initiating cells. 7 Nuclear factor-kappa B (NF-kB) comprises of a family of transcription factors 8 that have been widely implicated in various cellular processes including immunity, development, and oncogenesis.…”

Distinct genome protective vs. ribosome synthetic functions of the paralogous nucleolar proteins nucleostemin and GNL3L

“…The subsequent identification of GNL3L, the mammalian paralog of nucleostemin, broadened the landscape of possible functions of these two nucleolar GTP-binding proteins. Subsequent work on both nucleostemin and GNL3L (Lin et al, 2010;Ma and Pederson, 2007;Meng et al, 2011a;Meng et al, 2011b;Meng et al, 2008;Zhu et al, 2009;Zhu et al, 2006) drew attention to the involvement of both proteins in cell proliferation, although the direct roles of the proteins were not rigorously proven. At the same time, evidence appeared in Drosophila linking the invertebrate protein, GNL3, to ribosome biosynthesis (Rosby et al, 2009), and another report implicated mammalian nucleostemin in ribosome biosynthesis (Romanova et al, 2009a).…”