THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies

Abstract

Promyelocytic leukemia (PML) nuclear bodies (PML NBs) are discrete subnuclear domains organized by the promyelocytic leukemia protein PML, a tumor suppressor essential for multiple apoptotic pathways. We have recently described a novel family of cellular factors, the THAP proteins, characterized by the presence at their amino-terminus of an evolutionary conserved putative DNA-binding motif, designated THAP domain. Here, we report that THAP1 is a novel nuclear proapoptotic factor associated with PML NBs, which potentiates both serum withdrawal-and TNFa-induced apoptosis, and interacts with prostate-apoptosis-response-4 (Par-4), a well characterized proapoptotic factor, previously linked to prostate cancer and neurodegenerative diseases. We show that endogenous Par-4 colocalizes with ectopic THAP1 within PML NBs in primary endothelial cells and fibroblasts. In addition, we found that Par-4 is a component of PML NBs in blood vessels, a major site of PML expression in vivo. Finally, we investigated the role of the THAP domain in THAP1 activities and found that this putative DNA-binding domain is not required for Par-4 binding and localization within PML NBs, but is essential for THAP1 proapoptotic activity. Together, our results provide an unexpected link between a nuclear factor of the THAP family, the proapoptotic protein Par-4 and PML nuclear bodies.

The genetics of the dystonias – a review based on the new classification of the dystonias

“…Lifetime penetrance of this disorder is estimated to be approximately 60% with no sex differences identified 9 . The DYT6 gene (THAP1) consists of three exons and codes for the THAP1 protein 10,11 . THAP1 is a nuclear proapoptotic factor that potentiates tumor necrosis factor (TNF)-α-induced apoptosis and serum withdrawal-induced apoptosis 10 .…”

“…The DYT6 gene (THAP1) consists of three exons and codes for the THAP1 protein 10,11 . THAP1 is a nuclear proapoptotic factor that potentiates tumor necrosis factor (TNF)-α-induced apoptosis and serum withdrawal-induced apoptosis 10 . Although many of the biological functions of THAP proteins apart from their involvement in apoptotic pathways remain unknown, various findings have confirmed that they play an important role in cell proliferation 10,11 .…”

Structure-Function Analysis of the THAP Zinc Finger of THAP1, a Large C2CH DNA-binding Module Linked to Rb/E2F Pathways

“…This motif, designated THAP domain or THAP zinc finger, defines a previously uncharacterized large family of cellular factors with more than 100 distinct members in the animal kingdom (6,7). We showed that the THAP domain of THAP1, the prototype of the THAP family (8), possesses zinc-dependent sequence-specific DNA binding activity and recognizes a consensus DNA target sequence of 11 nucleotides (THABS, for the THAP1 binding sequence) (7), considerably larger than the 3-4 nucleotides motif typically recognized by classical C2H2 zinc fingers (2,7). Interestingly, the consensus C2CH signature of the THAP domain was identified in the sequence-specific DNA-binding domain of Drosophila P element transposase, suggesting the THAP zinc finger constitutes a novel example of a DNA-binding domain shared between cellular proteins and transposons from mobile genomic parasites (6,9).…”

Alternative Approaches to Modeling Hereditary Dystonias

“…This technique may also require a priori selection of infusion sites, and as such it is also a biased approach. Unfortunately, some of the most common dystonia genes code for proteins that function in a variety of processes important for cell signaling, stability, and maintenance [48,[77][78][79][80]. In these cases, finding a compound that inhibits a specific function of the protein of interest is likely to be difficult or even impossible.…”