Nuclear proteostasis in transcriptional dynamics

Nuclear proteostasis in transcriptional dynamics

Lab Sawarkar

Proteins are folded and stabilized by chaperones and degraded by proteasomal machinery. Both these important arms of protein homeostasis or proteostasis function not only in cytosol but also at chromatin, as recent exciting studies have shown. Our long-term goal is to systematically quantitate proteostasis at chromatin in the context of transcription. How these processes are regulated when the cellular environment changes during development, stress, ageing and disease will be investigated. In particular the following two aspects of proteostasis will be studied in detail.

RNA polymerase II, the machine that transcribes most of the coding genes, is shown to bind to individual genes as bands on Drosophila polytene chromosomes. What regulates the activity of this machine at every one of the promoters in the cell is a central question in biology today. We focus on the proteostasis of chromatin factors that regulate RNA pol II activity.

Chromatin-based chaperone network: The chromatin proteins controlling RNA pol II activity are stabilized by chaperones such as heat-shock protein 90 (Hsp90). Inhibitors of Hsp90 are in advanced clinical trials for cancer treatment implicating the chaperone in cancer pathology. Using a combination of proteomics, fly genetics and systems biology approaches, we are mapping the chromatin-based chaperone network and its influence on DNA transactions such as transcription and replication. We will elucidate how this network is integrated with the extra-nuclear signaling and how this affects cancer initiation and progression.

Chromatin-based degradation control: Cells respond to external environment by typically mounting a rapid transcriptional response. These processes require rapid removal of chromatin factors from specific loci, and hence are degraded at chromatin. How this process achieves the specificity and is regulated by external cues remains a mystery. We will utilize systematic approaches to decipher the mechanisms and controls operating. By providing synthetic and specific degradation machinery at chromatin, we will test the design principles of nuclear proteostasis.

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