TRIP6 and LPP, but not Zyxin, are present at a subset of telomeres in human cells

Abstract

T he protection of chromosome ends requires the inhibition of DNA damage responses at telomeres. This inhibition is exerted in great part by the shelterin complex, known to prevent inappropriate ATM and ATR activation. The molecular mechanisms by which shelterin protects telomeres are incompletely understood. Recently, we have implicated for the first time a class of molecules, LIM domain proteins, in telomere protection. This protection occurred through interaction with shelterin, possibly through POT1, and required the pair of LIM proteins TRIP6 and LPP, themselves part of the Zyxin family. The domain similarity between TRIP6, LPP and Zyxin led us to ask whether the latter also interacted with telomeres. Here, we show that there is specificity in the association of LIM proteins with telomeres: Zyxin, despite a high degree of similarity with TRIP6 and LPP, was not detected at telomeres, nor found in a complex with shelterin. TRIP6 and LPP, however, were detected by immunofluorescence at a small subset of telomeres, perhaps those that are critically short. We speculate that specific LIM proteins are part of complex events occurring in the context of the telomere dysfunction response and are possibly at play during the induction of senescence.

Defining the role of TRIP6 in cell physiology and cancer

“…Telomeres are nucleoprotein structures that protect chromosome ends, which are particularly vulnerable to progressive shortening during each round of DNA replication (telomere erosion) (Artandi and DePinho, 2010). Recently, Sheppard and colleagues uncovered an unanticipated role of TRIP6 in telomere protection (Sheppard and Loayza, 2010; Sheppard et al, 2011). At the very distal end of the telomere, a 300 bp single‐stranded portion (T‐loop) is present that prevents telomere ends from being recognized as break points by the DNA repair machinery (Karlseder, 2003).…”

“…The T‐loop is held together by several proteins: most notably TRF1 and TRF2 respectively, POT1 and TIN2, collectively referred to as the shelterin complex (Donate and Blasco, 2011). TRIP6 and LPP (but not zyxin) directly interact with POT1, TRF1, TRF2 and TIN2 in human cells, arguing for an association of TRIP6 with the whole shelterin complex (Sheppard and Loayza, 2010; Sheppard et al, 2011). TRIP6 and LPP depletion leads to telomere dysfunction‐induced foci and DNA damage responses, which are typical signs for telomere erosion (Sheppard and Loayza, 2010; Sheppard et al, 2011).…”

“…TRIP6 and LPP (but not zyxin) directly interact with POT1, TRF1, TRF2 and TIN2 in human cells, arguing for an association of TRIP6 with the whole shelterin complex (Sheppard and Loayza, 2010; Sheppard et al, 2011). TRIP6 and LPP depletion leads to telomere dysfunction‐induced foci and DNA damage responses, which are typical signs for telomere erosion (Sheppard and Loayza, 2010; Sheppard et al, 2011). Hence, apart from TRIP6 overexpression, as discussed above, down‐regulation or the loss of TRIP6 could provide means to enhance tumorigenesis and cancer progression by fostering telomere erosion and thus genomic instability.…”

The Zyxin‐related protein thyroid receptor interacting protein 6 (TRIP6) is overexpressed in Ewing's sarcoma and promotes migration, invasion and cell growth

“…In the nucleus, TRIP6 has transcriptional cofactor activity and regulates the transcriptional responses of these pathways (Kassel et al., ; Diefenbacher et al., , ; Willier et al., ). Moreover, intranuclear TRIP6, but not Zyxin, associates with proteins ensuring telomere protection and hence may play a role in genome stability (Sheppard and Loayza, ; Sheppard et al., ). Accordingly, TRIP6 is engaged in key cellular processes such as cell migration, invasion, proliferation, differentiation and survival.…”

LIM Protein Ajuba Participates in the Repression of the ATR-Mediated DNA Damage Response

“…Our laboratory has previously shown that members of a distinctive class of molecules called LIM proteins are implicated in telomere protection by repressing DDR at telomeres (Sheppard and Loayza, 2010; Sheppard et al, 2011). Specifically, LIM proteins TRIP6 and LPP belong to the Zyxin family (Kadrmas and Beckerle, 2004) and interact with the shelterin complex to prevent DDR activation at telomeres.…”