Post-translational modification of the C-terminal domain of RNA polymerase II : identification and cross talk




Mayfield, Joshua Edward

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RNA polymerase II is a highly regulated protein complex that transcribes all protein coding mRNA and many non-coding RNAs. A key mechanism that facilitates its activity is post-translational modification of the carboxyl-terminal domain of RNA polymerase II (CTD). This unstructured domain is conserved throughout eukaryotes and composed of repeats of the consensus amino acid heptad Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. This domain acts as a platform for the recruitment of transcriptional regulators that specifically recognize post-translational modification states of the CTD. The majority of our understanding of CTD modification comes from the use of phospho-specific antibodies, which provide identity and abundance information but give only low-resolution information for how these marks co-exist and interact at the molecular level. During my graduate work I sought to utilize the tools of chemical biology to investigate CTD modification in high resolution. Using a combination of chemical tools, analytical chemistry, and molecular biology I studied CTD modification in extremely high resolution. This work reveals the existence of interactions between CTD modifications, the influence of CTD sequence divergence on modification events, and presents initial data to support a role for previously encoded modifications to direct subsequent modification events



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