Our Science – Gottesman Website

Susan Gottesman, Ph.D.

Laboratory of Molecular Biology Head, Biochemical Genetics Section Laboratory Co-Chief Building 37, Room 5132 NCI-Bethesda Bethesda, MD 20892 Phone:   301-496-3524 Fax:   301-496-3875 E-Mail:   susang@helix.nih.gov Link: Other Homepage

Biography

Dr. Gottesman received her Ph.D. from the Department of Microbiology at Harvard University and became a postdoctoral fellow at the NIH. She then went to the Massachusetts Institute of Technology (MIT) as a research associate and returned to the NIH in 1976 as a senior investigator in the Laboratory of Molecular Biology, where she has remained. She was elected to the National Academy of Sciences in 1998 and the American Academy of Arts and Sciences in 1999 in recognition of her work on energy-dependent proteolysis.

Research

Small Regulatory RNAs and Energy-Dependent Proteolysis: Novel Modes for the Regulation of Gene Expression

Our laboratory has been interested in novel mechanisms for gene regulation and how these mechanisms contribute to global control circuits in Escherichia coli. For many years, the focus of the laboratory was energy-dependent proteolysis. In recent years, the focus has shifted to studying small regulatory RNAs. We first encountered these small RNAs when studying the regulation of synthesis of a substrate for the energy-dependent proteases, and it is quite possible that these two mechanisms frequently contribute to the regulation of the same genes.

This is exemplified in the regulation of RpoS, a stress sigma factor of E. coli,. RpoS is rapidly degraded during exponential growth by the ClpXP protease; this degradation is in turn regulated by the response regulator protein RssB. We have found that RssB affects degradation only of RpoS, and not of another ClpXP substrate, lambda O protein. This suggests that environmental and cell cycle regulation via changes in protein degradation may operate by modifying substrate availability rather than protease activity. In vitro collaborative studies with Dr. Sue Wickner demonstrate that RssB acts directly, first interacting with the substrate and then delivering it to the protease. Thus, regulated degradation probably is dependent on the activation of RssB, which appears to require phosphorylation. The signaling pathway for phosphorylation is under investigation.

In addition to this regulation of RpoS degradation, the translation of RpoS is positively regulated by at least two small RNAs. One of these, DsrA. is synthesized preferentially at low temperatures (<30 °C) and is necessary for the low-temperature expression of RpoS. DsrA modulates RpoS synthesis by positively affecting translation of this protein by pairing with parts of the RpoS untranslated leader. A second small RNA regulator of RpoS, RprA, has also been identified. RprA acts by a mechanism similar to that of DsrA in stimulating RpoS synthesis, but is regulated not by low temperature but by a two-component regulatory system responsive to cell surface status. Thus, these two small RNAs allow two very different environmental signals to be sensed for increased RpoS synthesis.

In collaboration with others, we have undertaken a genome-wide search for other small regulatory RNAs. We find that highly conserved stretches with the intergenic regions are reliable hallmarks of small RNAs. This study led to the identification of 17 novel small RNAs as well as 6 new, short mRNAs. The function of some of these new small RNAs is under study; a substantial number of them appear to be involved in translational regulation.
In another genome-wide collaborative study, we defined small RNAs that bind the RNA chaperone Hfq, used by fully 1/3 of the small RNAs in the cell. This led to identification of yet other, less conserved small RNAs. This work as well as our previous studies of DsrA and RprA suggest that small RNAs are important and underappreciated components of many regulatory circuits.

In addition to the small RNAs that regulate RpoS, our recent studies have been focused on new RNAs found in the global searches. One of these, RyhB, is synthesized only when iron is limiting (it is repressed by the Fur repressor). RyhB redirects cellular metabolism to respond to the iron limitation by down-regulating synthesis of non-essential proteins that use Fe. Small RNAs with the same physiological role may be very widespread; a collaborative study has found them in Pseudomonads and other related bacteria. In addition, studies on the mechanism of RyhB action demonstrate that both the small RNA and the target mRNA are turned over during use.


Collaborators on this research include Michael Maurizi, Gisela Storz, David Fitzgerald and Sue Wickner, NIH; Michael Vasil, Univ. of Colorado Health Sciences Center.

This page was last updated on 10/28/2008.