The prolyl cis/trans isomerase Pin1 regulates turnover of TRF1    and telomere maintenance Free

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Telomeres are DNA-protein structures at the ends of chromosomes and their deregulation has been implicated in cancer and aging. TRF1 is a telomeric DNA-binding protein that negatively regulates telomere length and also affects mitotic regulation. Post-translational modification of TRF1 including phosphorylation, ribosylation and ubiquitination regulates telomere maintenance and cell cycle control. Recently, it has been reported that the Fbx4-mediated ubiquitination of TRF1 alters the stability of TRF1 and regulates telomere maintenance. However, the pathway required for TRF1 degradation and the relevance of the turnover for telomere maintenance are still unknown.

Pin1 is a peptidyl-propyl cis-trans isomerase (PPIase) that isomerizes only phosphorylated Ser/Thr-Pro peptide bonds. These Pin1-induced conformational changes after phosphorylation can control many protein functions, including their catalytic activity levels, phosphorylation status, protein interaction, subcellular localization, and/or protein stability depending on the substrates. Pin1 is highly overexpressed in many human cancers and is important for the activation of multiple oncogenic pathways, indicating that Pin1 plays a key role in the pathogenesis of cancer.

Here, we report that TRF1 function is regulated by Pin1-mediated propyl isomerization. Pin1 interacts with TRF1 by phosphorylation dependent manner in vitro and in vivo. Amounts of TRF1 protein are increased in tissues examined from Pin1-deficient mice, in comparison with those from wild-type mice, indicating that TRF1 level is upregulated in Pin1 knockout mice. Furthermore, TRF1 expression is decreased and correlated with Pin1 overexpression in human breast cancer tissues, suggesting that a close relationship between Pin1 and TRF1 levels under both physiological and pathological conditions. Moreover, inhibition of Pin1 by RNA interference enhances TRF1 protein stability and results in telomere shortening. Thus, Pin1 is a novel negative regulator of TRF1 and its overexpression might contribute to the downregulation of TRF1 in tumors such as breast cancer as well as plays an essential role in regulating telomere length.