PAF1

What is PAF1 protein?

PAF1 (PAF1 homolog, Paf1/RNA polymerase II complex component) gene is a protein coding gene which situated on the long arm of chromosome 19 at locus 19q13. PAF1 is involved in multiple stages of transcription by RNA polymerase II, including transcriptional elongation. It interacts with the polymerase and is implicated in the regulation of development and maintenance of embryonic stem cell pluripotency. The PAF1 complex is composed of several subunits, including Paf1, Ctr9, Cdc73, Leo1, and Rtf1, with human PAF1C also containing an additional subunit Ski8. The PAF1 protein is consisted of 531 amino acids and its molecular mass is approximately 60.0 kDa.

What is the function of PAF1 protein?

PAF1C is involved in histone modifications such as the ubiquitination of histone H2B and methylation on histone H3 at lysine 4 (H3K4me3), which are important for the regulation of gene expression. PAF1C is involved in various cellular functions such as hematopoiesis and has been shown to stimulate the transcriptional activity of KMT2A/MLL1, promoting leukemogenesis through its association with KMT2A/MLL1-rearranged oncoproteins. PAF1C has oncogenic activity both in vivo and in vitro, indicating its potential role in cancer development. PAF1C is involved in mRNA 3' end formation, possibly through interactions with cleavage and polyadenylation factors.

Fig1. Paf1C regulates Pol II pause and release. (S Branden Van Oss, 2017)

PAF1 Related Signaling Pathway

PAF1, a component of the Paf1 complex (PAF1C), is intricately involved in various cellular processes, particularly in the regulation of gene expression through its role in the transcription pathway. PAF1C is connected to the Wnt signaling pathway, which plays a role in cell fate commitment and is often dysregulated in cancer. PAF1C plays a significant role in the transcription elongation process mediated by RNA polymerase II (RNAPII). It helps in the transition of RNAPII from a paused state to an elongation-competent state, which is crucial for gene expression regulation. PAF1C has been shown to regulate promoter-proximal pause release via enhancer activation, which is an essential mechanism for the activation of gene transcription.

PAF1 Related Diseases

PAF1 is associated with several diseases, particularly various types of cancer, due to its role in gene expression regulation and its involvement in cellular processes such as DNA repair and cell cycle control. Abnormal or mutated expression of PAF1 and its subunits, such as Ctr9, has been linked to the development of leukemia. PAF1C is involved in the cellular response to DNA damage, and its dysfunction may contribute to diseases where DNA repair mechanisms are compromised, such as various forms of cancer. Given the role of PAF1C in gene regulation and embryonic development, it may also be associated with developmental disorders related to gene expression dysregulation. PAF1 complex mutations are associated with pancreatic cancer, suggesting its role in the disease's pathology. The PAF1 complex's involvement in critical cellular processes suggests potential links to a broader range of cancers, although more research is needed to establish specific associations.

Bioapplications of PAF1

Given the association of PAF1 with cancer-related genes and its role in the regulation of gene expression, it presents a potential target for therapeutic intervention in cancer treatment. Understanding the molecular mechanisms of PAF1 could lead to the development of drugs that modulate its activity, impacting the behavior of cancer cells. Knowledge of PAF1's role in transcriptional regulation can be applied in genetic engineering to control gene expression in a targeted manner, with potential applications in biotechnology and synthetic biology. Understanding how PAF1 responds to environmental stressors can be important for toxicology, helping to predict how cells might react to pollutants or other environmental factors.

Case Study 1: Zhong Chen, 2021

RNA Polymerase II (Pol II) transcriptional recycling is a mechanism for which the required factors and contributions to overall gene expression levels are poorly understood. The researchers describe an in vitro methodology facilitating unbiased identification of putative RNA Pol II transcriptional recycling factors and quantitative measurement of transcriptional output from recycled transcriptional components. Proof-of-principle experiments identified PAF1 complex components among recycling factors and detected defective transcriptional output from Pol II recycling following PAF1 depletion. Dynamic ChIP-seq confirmed PAF1 silencing triggered defective Pol II recycling in human cells. Prostate tumors exhibited enhanced transcriptional recycling, which was attenuated by antibody-based PAF1 depletion.

Fig1. UCSC Genome Browser views of a representative PAF1 time course ChIP-seq in LNCaP-abl cells.

Fig2. The transcription recycling assay was performed using nuclear extracts with or without PAF1 depletion.

Case Study 2: Arokia Priyanka Vaz, 2016

Pancreatic differentiation 2 (PD2), an important subunit of the human PAF complex, was identified after differential screening analysis of 19q13 amplicon, and its overexpression induces oncogenic transformation of NIH3T3 cells, hence raising the possibility of a role for PD2 in tumorigenesis and metastasis. To test this hypothesis, the researchers analyzed here the functional role and clinical significance of PD2 in pancreatic ductal adenocarcinoma (PDAC) and its pathogenesis. Using immunohistochemical analysis, they found that PD2 is detected in the acini but not in the ducts in the normal pancreas. In human PDAC specimens, PD2 was instead primarily detected in the ducts (12/48 patients 25%; p-value < 0.0001), thereby showing that PDAC correlates with increased ductal expression of PD2. Consistently, PD2 expression was increased in telomerase-immortalized human pancreatic ductal cells (HPNE cells) modified to express the HPV16 E6 and E7 proteins, whose respective functions are to block p53 and RB. In addition, ectopic expression of PD2 in PDAC cells (Capan-1 and SW1990) led to increased clonogenicity and migration in vitro, and tumor growth and metastasis in vivo.

Fig3. PD2 expression was observed in all the cell lines.

Fig4. PD2 overexpression led to increased growth in cancer cells.

PAF1 has several biochemical functions, for example, RNA polymerase II core binding,chromatin binding,protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by PAF1 itself. We selected most functions PAF1 had, and list some proteins which have the same functions with PAF1. You can find most of the proteins on our site.

PAF1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PAF1 here. Most of them are supplied by our site. Hope this information will be useful for your research of PAF1.

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