Control of Gene Expression

BIOGRAPHY

ACADEMIC POSITION:
Buchler Professor of Transgenic Medicine, Department of Cell Biology, Albert Einstein College of Medicine

EDUCATION:
• BS (Physics), Yale University, 1958
• PhD (Biophysics), Massachusetts Institute of Technology, 1963
• Post-doctorate (Molecular Biology), Massachusetts Institute of Technology, 1963-1964, and Albert Einstein College of Medicine, 1964-1965

MEMBERSHIPS/AWARDS:
• NSF Pre-doctoral Fellow, 1958-1963
• NSF Post-doctoral Fellow, 1964- 1965
• Guggenheim Fellow, 1971- 1972
• American Cancer Society Faculty Research Associate, 1971- 1977
• Orton K Stark Lecturer, Miami University, Ohio, 1986
• Judith & Burton P Resnick Chair in Cell Biology, 1991- 2000
• Joseph & Gertrud Buchler Chair in Transgenic Medicine, 2000-present
• Fellow, American Academy of Microbiology, 2001-

RESEARCH INTERESTS:
The ribosome is a molecular machine composed of 4 RNA molecules and 78 different proteins. The construction of a ribosome involves the integration of fundamental cellular processes: the transcription and processing of ribosomal RNA, the transcription, processing and translation of the mRNAs for ribosomal proteins, the assembly of the ribosomal proteins with the ribosomal RNAs, etc. In the yeast Saccharomyces cerevisiae, the synthesis of ribosomes consumes an extraordinary proportion of the cell's resources, accounting for >70% of all transcription, about 50% of all Pol II transcription, and >90% of all pre-mRNA splicing. We have used the genetic/biochemical approaches uniquely available in this organism to study the multiple levels of regulation that control this process. Our current research emphasizes two aspects of ribosome synthesis that will contribute to our understanding of the fundamental aspects of cell growth and regulation:

1) Co-ordinate regulation: One of the biologically interesting aspects of ribosome biosynthesis is that the 78 ribosomal proteins, encoded in 137 genes, must be provided in equimolar amounts with each other, and with rRNA. Amounts count! Over expression of a given ribosomal protein is frequently deleterious to cell growth; under expression will limit the production of ribosomes. One of our key questions currently is how this high degree of co-ordinate production is carried out. We, and others, have shown that most, BUT NOT ALL, of the RP genes are transcribed under the control of three proteins, Rap1, Fhl1, and Ifh1. Interestingly, Ifh1p, which is likely to be the transcriptional activating factor, is also found as a complex with proteins that are known to be involved with rRNA transcription and processing. We hypothesize that this interaction is the link that couples rRNA transcription with RP gene transcription, an absolutely critical function for efficient cell growth. Current experiments are aimed to test this hypothesis.

2) Quality Control and Degradation: We recently showed that the insufficient supply of a single ribosomal protein can have a strong effect on the regulation of ribosome synthesis. This led us to realize that the partial deficiency of a single ribosomal protein must lead to the production of many defective ribosomes which must be (A) detected and (B) degraded. Little is known about either process, although the exosome (for the RNA) and the proteosome (for the protein) are likely candidates. We are using Synthetic Genetic Analysis (SGA) to determine the proteins involved in each process, and to understand the biochemical and biological basis of the extreme balance that ribosome synthesis implies.