TIN2, a new regulator of telomere length in human cells

Abstract

Telomeres are DNA-protein structures that cap linear chromosomes and are essential for maintaining genomic stability and cell phenotype. We identified a novel human telomereassociated protein, TIN2, by interaction cloning using the telomeric DNA-binding-protein TRF1 as a bait. TIN2 interacted with TRF1 in vitro and in cells, and co-localized with TRF1 in nuclei and metaphase chromosomes. A mutant TIN2 that lacks amino-terminal sequences effects elongated human telomeres in a telomerase-dependent manner. Our findings suggest that TRF1 is insufficient for control of telomere length in human cells, and that TIN2 is an essential mediator of TRF1 function.

Cancer and aging: the importance of telomeres in genome maintenance

“…Recently, TIN2 was found to bind TRF2 [60], in addition to directly interacting with TRF1 [51,52] ( Fig. 2).…”

“…TRF1 almost certainly regulates telomere structure via its interactions with other proteins. Among the most important of these interactions are its ability to bind the telomereassociated protein TIN2 [51,52]. TIN2 does not bind telomeric DNA directly.…”

“…The TIN2-TRF2 interaction is very likely crucial for both TRF2 and TRF1 functions in vivo. Depending on the level of expression and type of mutation, dominant negative forms of TIN2, like dominant negative TRF1, can extend telomere length [51], or, like dominant negative TRF2, can induce pervasive telomere uncapping [60]. Thus, TIN2 may link the functions of TRF1 and TRF2.…”

“…Nonetheless, perturbations to either TRF1 or TRF2, or their associated proteins POT1, RAP1 or TIN2, influence both telomere length and capping [50,51,60,61,[64][65][66][67] A major gap in our knowledge of telomere composition is how the myriad proteins that associate with telomeres ( Fig. 3) organize.…”

Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2

“…Inhibition of TRF2 by expression of a dominant-negative form of TRF2 results in loss of the Gstrand overhang, induces end-to-end chromosome fusions generated by DNA ligase IV-dependent nonhomologous end joining, and rapidly initiates a p53-and ATM-dependent apoptotic pathway (35,54,60). Some additional regulators of telomere length dynamics have been identified in human cells: the TRF1 interacting factors PinX1 and TIN2, both shown to regulate telomere length in a telomerase-dependent manner, and hRAP1, which is recruited to telomeres by TRF2 (37,38,64).…”