TRF1 Controls Telomere Length and Mitotic Fidelity in Epithelial Homeostasis

Abstract

TRF1 is a component of the shelterin complex at mammalian telomeres; however, a role for TRF1 in telomere biology in the context of the organism is unclear. In this study, we generated mice with transgenic TRF1 expression targeted to epithelial tissues (K5TRF1 mice). K5TRF1 mice have shorter telomeres in the epidermis than wild-type controls do, and these are rescued in the absence of the XPF nuclease, indicating that TRF1 acts as a negative regulator of telomere length by controlling XPF activity at telomeres, similar to what was previously described for TRF2-overexpressing mice (K5TRF2 mice). K5TRF1 cells also show increased end-toend chromosomal fusions, multitelomeric signals, and increased telomere recombination, indicating an impact of TRF1 on telomere integrity, again similar to the case in K5TRF2 cells. Intriguingly, K5TRF1 cells, but not K5TRF2 cells, show increased mitotic spindle aberrations. TRF1 colocalizes with the spindle assembly checkpoint proteins BubR1 and Mad2 at mouse telomeres, indicating a link between telomeres and the mitotic spindle. Together, these results demonstrate that TRF1, like TRF2, negatively regulates telomere length in vivo by controlling the action of the XPF nuclease at telomeres; in addition, TRF1 has a unique role in the mitotic spindle checkpoint.

Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice

“…Our results are in agreement with those obtained previously with TRF1-deleted ES cells (Karlseder et al 2003), which also reported normal-length telomeres in the absence of TRF1. On the other hand, TRF1 overexpression in mice leads to telomere shortening mediated by the XPF nuclease, suggesting a model in which TRF1 titrates XPF levels at telomeres (Munoz et al 2009). Although TRF1 deletion could conceivably lead to decreased XPF activity at telomeres, this is unlikely to have any effect on telomere length, as we and others have shown previously that XPFdeficient mice have normal-length telomeres (Zhu et al 2003;Munoz et al 2005Munoz et al , 2009.…”

“…Extensive TRF1 overexpression data have established a model in which aberrantly overexpressed TRF1 acts as a negative regulator of telomere length (de Lange 2005;Munoz et al 2009). Here we show, however, that TRF1 abrogation does not result in telomere length changes in both MEFs and the context of mouse tissues.…”

“…TRF1 has been attributed roles in telomere length regulation, telomere cohesion, and telomere silencing, among others (van Steensel and de Lange 1997; Koering et al 2002;Dynek and Smith 2004;Schoeftner and Blasco 2008;Munoz et al 2009). Most of these studies have been based on TRF1 overexpression experiments in both cells and mice.…”

“…2A-E). Given the previously proposed role of TRF1 as a negative regulator of telomere length (van Steensel and de Lange 1997;Smogorzewska et al 2000;Ancelin et al 2002;Munoz et al 2009), we addressed the impact of TRF1 deletion on telomere length by performing telomere Q-FISH on metaphases (Materials and Methods). TRF1 D/D -Cre-LT MEF showed increased telomere fluorescence when considering all individual telomere signals, including the fusions (Fig.…”

“…Extensive cell-based in vitro studies using overexpression of TRF1 alleles have suggested a role for TRF1 as a negative regulator of telomere length (van Steensel and de Lange 1997;Smogorzewska et al 2000;Ancelin et al 2002). More recently, TRF1 overexpression in the context of transgenic mouse tissues was also shown to lead to telomere shortening mediated by the XPF nuclease (Munoz et al 2009). Post-transcriptional modification of TRF1 by tankyrases 1 and 2, which poly-ADPribosylate TRF1, can regulate its binding to telomeres, thereby influencing telomere length and sister telomere cohesion (Smith et al 1998;Cook et al 2002).…”