The Telomere Repeat Binding Protein Trf1 Interacts with the Spindle Checkpoint Protein Mad1 and Nek2 Mitotic Kinase

Abstract

The mitotic spindle checkpoint arrests cells in metaphase until all kinetochores are correctly attached to spindle fibres. In a search for new components of the spindle checkpoint, based on protein interaction, we have identified mouse Telomeric Repeat Binding Factor 1 (Trf1) as a protein that interacts directly with the spindle checkpoint protein Mad1 and the mitotic kinase Nek2. Trf1 has a role in the regulation of telomere length, but has also been implicated in cell cycle regulation. These interactions now provide a direct link between telomere length regulation and the control of mitotic progression.

TRF1 Controls Telomere Length and Mitotic Fidelity in Epithelial Homeostasis

“…In addition, Mad2, a critical regulator of SAC inactivation, also colo- calized with TRF1 at mouse telomeres. This is in agreement with previous findings showing a TRF1-Mad1 interaction in human cells (43). In contrast to K5TRF1 cells, K5TRF2 cells did not show mitotic defects, suggesting a putative role for TRF1 in spindle formation or chromosome alignment.…”

“…K5TRF1 but not K5TRF2 cells show aberrant mitotic spindles. In addition to its telomeric roles, TRF1 has been suggested to be part of the mitotic spindle checkpoint (40,43). To address whether K5TRF1 mice showed any defects in spindle formation during mitosis, we first studied the percentage of K5TRF1 keratinocytes showing mitotic spindle defects compared to wild-type controls.…”

“…In addition, TRF1 regulates sister telomere cohesion at telomeres through posttranscriptional modification by tankyrase 1 (10,49). TRF1 has also been shown to interact with components of the mitotic spindle, including the mitotic kinase NIMA and the spindle regulator Mad1 (40,43). Furthermore, TRF1 has been shown to interact with microtubules and to control microtubule polymerization (40).…”

Role of the TRF2 Telomeric Protein in Cancer and Aging

“…4 These telomere-independent roles of TRF1 may be related to a suggested role for TRF1 and some TRF1-interacting proteins in mitosis. 5,6 Interestingly, the expression of TRF1, TIN2, Pot1 and tankyrase is upregulated in a number of human tumors, although whether the increased levels of these factors contribute to tumorigenesis remains unknown. 7 A putative role for these proteins in aging remains unexplored to date.…”

The 68-kDa Telomeric Repeat Binding Factor 1 (TRF1)-associated Protein (TAP68) Interacts with and Recruits TRF1 to the Spindle Pole during Mitosis

“…The spindle pole localization of TRF1 has been reported more than 10 years ago (4,17). Later, it was reported that TRF1 interacts with spindle assembly checkpoint protein Mad1 and key mitotic kinase NEK2A (NIMA-related kinase 2) (18,19). Recently, accumulating evidence suggests that TRF1 is required for faithful mitotic progression (20 -22).…”