Project information
RNA Polymerase II at the Intersection of Transcription and Disease: An In-depth Examination of its C-Terminal Domain (POL2PHASE)

The genetic interplay between neurodegenerative diseases, cancers, and viral infections is increasingly being linked to proteins' intrinsically disordered regions (IDRs). These proteins have been visualized to phase separate into condensed droplets via microscopy imaging. Though Molecular Dynamics (MD) simulations model IDRs accurately, they have largely sidestepped multi-domain proteins which comprise approximately 30% of the eukaryotic proteome. This study seeks to bridge the gap by developing a methodology for characterizing multi-domain protein condensates, primarily focusing on the RNA polymerase II (Pol II) - a protein pivotal in cellular function through transcription. The proposal will explore the C-Terminal Domain (CTD) of Pol II, aiming to elucidate its role in regulating the transcription factors (TFs) during various stages of transcription. Additionally, the importance of post-translational modifications (PTMs) on CTD and their implications in diseases such as amyotrophic lateral sclerosis (ALS) and myotonic dystrophy type 1 (DM1) will be investigated. Leveraging a coarse-graining approach in MD simulations and collaborating with experimental groups at Central European Institute of Technology – Masaryk University (CEITEC MU), this research aspires to advance our understanding of aberrant condensates related to CTD, ultimately informing therapeutic strategies and drug development processes.