RNA polymerase II-associated factor 1 complex (PAF1C)

The RNA polymerase II-associated factor 1 complex (PAF1C) is a highly conserved multi-subunit assembly consisting of PAF1, CTR9, LEO1, CDC73 (parafibromin), and WDR61 (SKI8) that coordinates various stages of the RNA polymerase II transcription cycle (Tomson & Arndt, 2013; UniProt, 2024). It primarily functions during transcription elongation, where it serves as a scaffold to recruit chromatin-modifying enzymes responsible for histone H2B monoubiquitination and H3K4/H3K79 methylation, thereby maintaining an active chromatin state (Van Oss et al., 2017). Beyond transcription, PAF1C is involved in mRNA 3-end processing, polyadenylation, and nuclear export, ensuring the proper maturation and transport of transcripts (Chaudhary et al., 2007). In oncology, the complex is frequently overexpressed and acts as an oncogenic driver in several malignancies, including MLL-rearranged leukemias and pancreatic, breast, and gastric cancers, by promoting the expression of key oncogenes like MYC (Ding et al., 2013). Mutations in the CDC73 subunit are specifically linked to hyperparathyroidism-jaw tumor syndrome, highlighting its role as a tumor suppressor in specific contexts (Newey et al., 2010). Consequently, PAF1C has emerged as a promising therapeutic target, with current drug discovery efforts focusing on small-molecule inhibitors like iPAF1C and PROTACs designed to disrupt the complex or degrade its core subunits to reprogram the transcriptional landscape of malignant cells (Kanda et al., 2022).

Other names

PAF1 complexPolymerase-associated factor 1 complexPAF complexPD2/PAF1 complex

Inhibition of complex assembly through small molecules or targeted proteasomal degradation of core subunits (PROTACs) to suppress the transcription of oncogenic drivers.