Michael T. Howard, Ph.D.
Research Assistant Professor

Contribution to Society

The information contained within the human genome is decoded in a highly regulated and controlled manner. While the basic rules of decoding have been known for many decades, recent research is revealing a level of hidden complexity in which RNA signals and trans-acting factors can alter conventional protein synthesis to control gene expression. These findings have significant implications for our understanding of normal gene expression, and importantly, are providing insight into the molecular consequences of genetic mutations which lead to human disease.

Research Summary

The genetic code as presented in text books assumes genes are decoded by a linear mechanism such that translation initiates at a start codon and progresses three nucleotides at a time until a stop codon is encountered. However, the genetic code is far from universal and a significant number of genes have recently been identified in which the rules of the “universal” genetic code are altered as a means to control gene expression.

A recent significant effort in our laboratory is to understand the mechanism by which UGA codons (normally decoded as stop codons) are redefined to encode the 21 st amino acid selenocysteine. The selenocysteine residue is a highly reactive amino acid at physiological pH which is often utilized for specific enzymatic reactions. Selenoproteins play a role in many essential biological functions including protection against oxidative damage, production/interconversion of thyroid hormones, and normal muscle development,. We are actively investigation the mechanisms of selenocysteine insertion and its regulation using a combination of biochemical, genetic, and cell based methodologies.

The insight gained from studying these, and other examples, of altered translation are also proving useful for the development of innovative small molecule and antisense based therapeutic approaches to suppressing disease causing genetic mutations. By mimicking the natural signals which cause stop codon redefinition, premature stop codon mutations can be “read through” during translation to produce functional full length proteins. Likewise, translational frameshifting induced near a frameshift mutation can revert the protein synthesis machinery back into the correct reading frame. The result is restored expression of functional protein from alleles containing disease causing mutations. In collaboration with Dr. Kevin Flanigan ( University of Utah), we are testing several of these novel approaches as a means to suppress genetic mutations which cause Duchenne and Becker Muscular Dystrophies.

Recent Publications

Wooding S, Bufe B, Grassi C, Howard MT, Stone AC, Vazquez M, et al.. Independent evolution of bitter-taste sensitivity in humans and chimpanzees. Nature 2005; 440: 930-934.

 Petros LM, Howard MT, Gesteland RF, and Atkins JF. Polyamine sensing during antizyme mRNA programmed frameshifting. Biochem. Biophys. Research Comm. 2005; 338: 1478-1489.

Howard MT, Aggarwal, G, Anderson CB, Khatri S, Flanigan KM, and Atkins JF. Recoding elements located adjacent to a subset of eukaryal selenocysteine-specifying UGA codons. EMBO J 2005; 24:1596-1607.

Baranov PV, Henderson CM, Anderson CB, Gesteland RF, Atkins JF, and Howard MT. Programmed Ribosomal Frameshifting in Decoding the SARS-CoV Genome. Virology 2005; 332: 498-510.

Howard MT, Gesteland RF, Atkins JF. Efficient stimulation of site-specific ribosomal frameshifting by antisense oligonucleotides. RNA 2004; 10:1053-1061.

Howard MT, Malik N, Anderson CB, Voskuil JLA, Atkins JF, Gibbons RJ. Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation. Journal of Medical Genetics 2004;41:951-956

Howard MT, Anderson CB, Fass U, Khatri S, Gesteland RF, Atkins JF, Flanigan KM. Readthrough of Dystrophin Stop Codon Mutations Induced by Aminoglycosides. Annals of Neurology 2004;55:422-426.

Atkins JF, Baranov PV, Fayet O, Herr AJ, Howard MT, Ivanov IP, Matsufuji S, Miller WA, Moore BM, Prére MF, Wills NM, Jhou J, Gesteland RF. Overriding standard decoding: Implications of recoding for ribosome function and enrichment of gene expression. Cold Spring Harbor Symposia on Quantitative Biology. 2001;Volume LXVI:217-232.

Howard MT, Shirts BH, Zhou J, Carlson CL, Matsufuji S, Gesteland RF, Weeks RS, Atkins JF. Cell culture analysis of the regulatory frameshift event required for the expression of mammalian antizymes. Genes to Cells 2001;6:931-941.

Howard MT, Shirts BH, Petros LM, Flanigan KM, Gesteland RF, Atkins JF. Sequence specificity of aminoglycoside induced stop codon readthrough: Potential implications for treatment of Duchenne Muscular Dystrophy. Annals of Neurology 2000;48:164-169.