Disease relevance of THAP1

• Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families [1].

High impact information on THAP1

• The THAP domain: a novel protein motif with similarity to the DNA-binding domain of P element transposase [2].
• Together with previous genetic data obtained in C. elegans, our results suggest that cellular THAP proteins may function as zinc-dependent sequence-specific DNA-binding factors with roles in proliferation, apoptosis, cell cycle, chromosome segregation, chromatin modification, and transcriptional regulation [3].
• In addition, we demonstrate the biochemical function of the THAP domain as a zinc-dependent sequence-specific DNA-binding domain belonging to the zinc-finger superfamily [3].
• In vitro binding-site selection allowed us to identify an 11-nucleotide consensus DNA-binding sequence specifically recognized by the THAP domain of human THAP1 [3].
• The four other conserved residues (P, W, F, and P), which define the THAP consensus sequence, were also found to be required for DNA binding [3].

Biological context of THAP1

• Here, we show that THAP1 is a physiologic regulator of EC proliferation and cell-cycle progression, 2 essential processes for angiogenesis [4].
• The similar phenotypes observed after THAP1 overexpression and silencing suggest that an optimal range of THAP1 expression is essential for EC proliferation [4].
• Together, these data provide the first links in mammals among THAP proteins, cell proliferation, and pRB/E2F cell-cycle pathways [4].
• This is the first demonstration of the transcriptional regulatory properties of a human THAP domain protein, and a critical identification of a potential transducer of the repressive signal of hypoacetylated histone H4 in higher eukaryotes [5].
• We show that the use of 2',4',6'-trihydroxyacetophenone (THAP) as MALDI matrix allows analysis of cross-linked peptide-RNA oligonucleotides in the reflectron mode at high resolution, enabling sufficient accuracy to assign unambiguously cross-linked RNA sequences [6].

Anatomical context of THAP1

• We show that endogenous Par-4 colocalizes with ectopic THAP1 within PML NBs in primary endothelial cells and fibroblasts [7].
• We recently cloned a novel human nuclear factor (designated THAP1) from postcapillary venule endothelial cells (ECs) that contains a DNA-binding THAP domain, shared with zebrafish E2F6 and several Caenorhabditis elegans proteins interacting genetically with retinoblastoma gene product (pRB) [4].

Associations of THAP1 with chemical compounds

• Negative-ion spectra of pure mono-, di-, and trisialylated oligosaccharides were acquired with either 6-aza-2-thiothymine or 2',4',6'-trihydroxyacetophenone (THAP) in the linear mode [8].
• In addition, THAP offered improved sensitivity for detection of acidic glycopeptides over alpha-cyano-4-hydroxycinnamic acid [8].
• Incorporation of ammonium citrate into the matrix, along with vacuum drying of the sample, was required in order to obtain maximum sensitivity with THAP [8].
• We show that use of the salt-tolerant matrix 2,4,6-trihydroxyacetophenone containing diammonium citrate (THAP/DAC) as an alternative to alpha-cyanohydroxycinnamic acid (HCCA) reduces the need for extensive washing of ZipTip-bound peptides or additional on-target sample clean-up steps [9].
• We demonstrated the utility of using the THAP/DAC MALDI matrix for peptide sequencing with DNA polymerase beta tryptic peptide mixture, as well as tryptic peptides derived from Xiphophorus maculatus brain extract proteins previously separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) [9].
• The combination of the mutagenesis and NMR data allowed the mapping of the DNA binding interface of the THAP zinc finger to a highly positively charged area harboring multiple lysine and arginine residues [10].

Other interactions of THAP1

• Retroviral-mediated gene transfer of THAP1 into primary human ECs inhibited proliferation, and large-scale expression profiling with microarrays revealed that THAP1-mediated growth inhibition is due to coordinated repression of pRB/E2F cell-cycle target genes [4].

References