Curriculum Vitae

Kristian E. Baker, Ph.D. (Principle Investigator)

Center for RNA Molecular Biology, Case Western Reserve University, School of Medicine, Wood Bldg.  W113, 10900 Euclid Ave., Cleveland OH 44106-4960, USA

E keb22@case.edu

P 216.368.0277

F 216.368.2010

PRIMARY APPOINTMENT

Assistant Professor in The Center for RNA Molecular Biology

EDUCATION

University of Regina, Saskatchewan Canada 1987-1992 B.Sc. Hons. Chemistry (Biochemistry)

University of Regina, Saskatchewan Canada 1992-1994 M.Sc. (Genetics/Biochemistry)

University of British Columbia, Vancouver Canada 1994-2002 Ph.D. (Genetics)

Howard Hughes Medical Institute/University of Arizona 2002-2005 Post-doctoral Fellow

BIO

It is becoming increasingly apparent that controlling gene expression by way of regulating mRNA function is critical for cell growth and adaptation. Regulation of mRNA metabolism can occur at numerous control points, such as during transcription, transport, translation, and degradation, and can involve highly complex molecular mechanisms. My interest in mRNA and how the molecule is managed by the cell has been the underlying theme of research throughout my career. Below are several examples of regulated gene expression that occur at the level of mRNA for which I have participated in studying.

Repression of mRNA translation

In the bacteria Escherichia coli and Salmonella Typhimurium, translation of pyrD mRNA (encoding an enzyme required for pyrimidine nucleotide biosynthesis) is repressed by RNA secondary structure that differentially forms at the 5’ end of the mRNA dependent upon the intracellular level of pyrimidine nucleotides (i.e. CTP & UTP). The stemloop structure precludes ribosome binding and, thus, translation of the mRNA, and its formation is dependent upon the position of transcriptional initiation by RNA polymerase. This mechanism for regulating pyrD expression involving pyrimidine-regulated transcriptional start-site selection by RNA polymerase, RNA secondary structure and translational repression provides an autoregulatory mechanism to ensure sufficient levels of pyrimidine nucleotide in the cell independent of any additional regulatory proteins.

Mechanisms and consequences of mRNA alternative splicing

Alternative splicing is the process by which exons of pre-mRNA are spliced together in different arrangements to produce mRNAs that can encode structurally and functionally distinct protein products. Importantly, alternative splicing is believed to account, in part, for the great macromolecular and cellular complexity of higher eukaryotic organisms. For the cell adhesion molecule, CD44, a striking correlation exists between the presence of certain alternatively spliced isoforms on the surface of tumor cells and both metastatic propensity and poor disease prognosis. Characterization of the cis-acting sequences within the CD44 mRNA that dictate its splicing pattern under different cellular conditions coupled with discovery of the trans-acting cellular factors which mediate the events are advancing our understanding of the role of CD44 in oncogenesis and may lead to the identification of new targets for therapeutic intervention.

mRNA degradation

The degradation of mRNA is necessary for the salvage and recycling of ribonucleotides, but, more importantly, it is crucial for proper gene regulation; mRNAs that are not subject to regulated translation must be eliminated in order to stop the production of their encoded polypeptide. In E. coli, the degradation of most, if not all, mRNA is initiated by an endonucleolytic cleavage catalyzed by the ribonuclease, RNase E, and mRNA stability is tightly correlated with mRNA translation. The relationship between mRNA translation and stability is important for ensuring that mRNAs that encode polypeptides needed by the cell are generally resistant to decay while mRNAs no longer required and that are not actively translated are targets for rapid degradation.

mRNA nucleo-cytoplasmic transport

Transport of mRNA from the nucleus is necessary for its translation in the cytoplasm and provides an ideal control point to ensure that nuclear RNA metabolic events (i.e. transcription, 3’ end formation, splicing) have occurred properly. The protein Apq12p was identified in Saccharomyces cerevisiae is a novel factor localized to the nuclear periphery that plays a role in nucleo-cytoplasmic mRNA transport. Interesting, yeast in which the APQ12 gene is deleted display aberrant cell morphology and abnormalities in nuclear DNA. New data has revealed genetic links between APQ12 and chromosome stability and cell cycle progression, suggesting that mRNA transport might, in some manner, be coupled to cell growth.

Nonsense-mediated mRNA decay

Presently, my research focuses on elucidating the molecular mechanisms in yeast that underlie the recognition and rapid degradation of mRNAs harboring a premature translational termination codon. Nonsense-mediated mRNA decay (NMD) is a highly conserved quality control mechanism that acts to eliminate mRNAs that fail to encode a proper polypeptide. I am particularly interested in identifying the environment that contributes to recognition of a premature termination codon as aberrant and how the recognition event leads to changes to the mRNA that result in its rapid decay.

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