Genes contain instructions for building proteins, which are the workhorses of our cells. Proteins carry out a vast array of functions, from providing structural support to catalyzing chemical reactions and transmitting signals throughout the body. Studying individual proteins and their roles provides insights into how our bodies function normally and what goes awry in various conditions.
What is TAF1?
TAF1 stands for TATA-binding protein associated factor 1. It is a large protein, encoded by the TAF1 gene in humans, and is a component of a larger assembly called Transcription Factor II D (TFIID). TFIID is a multiprotein complex that initiates the transcription of protein-coding genes. This complex is composed of the TATA-binding protein (TBP) and a group of TBP-associated factors, or TAFs, including TAF1.
TAF1 is the largest subunit of the TFIID complex, serving as a core scaffold for its assembly. It helps nucleate the formation of the complex, which recognizes specific sequences on gene promoters. TAF1 also forms a subcomplex with TAF7 and TAF2 that binds to promoter DNA. TFIID, with TAF1 as a central part, plays an important role in positioning RNA polymerase II correctly at the start of a gene, an essential step for gene expression.
How TAF1 Regulates Genes
TAF1 plays a multifaceted role in controlling gene expression. As part of the TFIID complex, it helps initiate transcription, the process where genetic information from DNA is copied into RNA. TAF1’s involvement extends beyond simply binding to DNA; it possesses several enzymatic activities that modify other molecules involved in gene regulation.
TAF1’s intrinsic protein kinase activity is found in both its N-terminal and C-terminal regions. This kinase adds phosphate groups to other proteins, such as p53 and components of the general transcription machinery like TFIIF. Phosphorylation of p53 by TAF1 leads to its dissociation from certain gene promoters, thereby influencing gene transcription. TAF1 also interacts with and phosphorylates other transcription factors, including E2F1 and FOXM1, affecting their ability to occupy gene promoters and regulate target genes.
TAF1 also possesses histone acetyltransferase (HAT) activity, which influences DNA packaging. Histones are proteins around which DNA is wound, and their acetylation opens the DNA structure, making genes more accessible for transcription. Specifically, TAF1’s HAT activity can acetylate histones H3 and H4, facilitating the binding of other transcription factors to promoter regions, such as the Sp1 sites of the cyclin D1 promoter. This activity enables TFIID to access and regulate gene expression within densely packed chromatin.
TAF1 exhibits ubiquitin ligase activity, which is involved in regulating protein degradation. It can act as a ubiquitin-activating and conjugating enzyme, participating in the monoubiquitination of histone H1 and increasing the total amount of ubiquitinated androgen receptor within prostate cancer cells. These diverse enzymatic functions highlight TAF1’s important role in fine-tuning gene expression and ensuring proper cellular processes.
TAF1 and Neurological Conditions
Dysfunction of the TAF1 protein is linked to X-linked Dystonia-Parkinsonism (XDP), a neurodegenerative disorder primarily affecting individuals of Filipino descent. This condition is caused by specific genetic changes in the TAF1 gene, particularly an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This insertion, along with other non-coding sequence variations, is inherited as a common haplotype in all reported XDP cases.
The SVA retrotransposon insertion leads to abnormal splicing and reduced expression of the full-length TAF1 mRNA transcript, particularly a neuron-specific isoform called N-TAF1. This reduction is observed in the caudate nucleus of XDP patients and in patient-derived neural stem cells, indicating an impairment in neuronal TAF1 expression at early developmental stages. The decreased TAF1 function is thought to disrupt the regulation of genes within neurons, leading to the eventual death of these cells, especially in the caudate nucleus and putamen regions of the brain.
XDP manifests in adulthood, with an average age of onset around 39.7 years, though it can range from 12 to 79 years. The most common symptoms include involuntary muscle contractions, known as dystonia, which often begins focally and can spread throughout the body. As the disease progresses, patients may also develop Parkinson’s-like symptoms, such as tremors and slow movement, which can eventually predominate. Understanding the precise mechanisms by which TAF1 dysfunction leads to these neurological issues is important for developing diagnostic tools and therapeutic strategies for XDP.