The Gottesman laboratory studies transcription termination in E. coli. They show that failure to release RNAP leads to formation of chromosomal DNA DSB. This is related to collapse of the replication fork at the site of the arrested RNAP. Under certain circumstances, an arrested RNAP can cause an array of RNAP to form that extends to the promoter, blocking transcription initiation. They show that most transcription termination in E. coli is required to prevent expression of lethal cryptic prophage genes. Removal of these prophages enhances resistance to the antibiotic bicyclomycin, an inhibitor of the RNAP release factor, Rho. The Gottesman laboratory also solved the structure of the transcription elongation factors NusE/S10 and NusB in complex, and demonstrated that NusE is the active component of the complex. Finally, they show that NusG binds both RNAP and NusE/S10, thus linking transcription and translation.
The Gottesman laboratory is also interested in the link betTheyen repair of DNA double- strand breaks (DSB) and DNA methylation. They find that a significant fraction of repaired genes become hypermethylated and silenced. They show that DNA Methyl Transferase I is recruited to the DSB during repair and is responsible for silencing.
Other aspects of DNA repair are also under investigation. Dr. Gottesman and his lab demonstrate repair of inter-strand DNA crosslink’s (ICL) in a cell-free Xenopus oocyte extract, and show that it involves extensive DNA resection and error-free DNA synthesis. Repair does not entail origin-initiated DNA synthesis, but is dependent on the Fanconi Anemia protein complex. They have also shown that DNA resection following a DSB requires the CtIP protein in S phase but not in M phase.
Dr. Gottesman and his lab study the role of AKAP anchoring proteins in signal transduction. AKAPs direct signals to different parts of the eukaryotic cell, and are of critical importance in transmission of these signals to their targets. Our interest is focused on AKAP121, which is associated with mitochondria. AKAP121 diverts EGF signaling from nucleus to mitochondria. It also regulates protein tyrosine phosphatase DI (PTPD1). PTPD1, which is an activator of src, promotes cell migration and metastases and is highly up-regulated in bladder cancer.