Labsite http://www.houlaboratory.org/

We are interested in the specificity of translation of the genetic code, focusing on the questions of how tRNAs are synthesized, matured, modified, aminoacylated, and function on the ribosome.

The tRNA molecules are essential for the specificity of decoding, which is the key determinant in the speed and quality of cell growth. Elevated levels of tRNAs can lead to cancer, while deficiency in tRNAs can lead to cell toxicity.

How are tRNAs synthesized and matured? How are they selectively charged with amino acids? How do they enter the ribosome, and how does their dynamics affect the decoding specificity? These questions have direct implications on diseases and origins of life.

The central aim of our research is to investigate the above questions at the fundamental level: what does it take to achieve the specificity of tRNA at each step of decoding? To address this fundamental question, we focus on the following enzymes: (1) the m1G37 methyl transferase, which synthesizes the m1G37 modification that is essential for the specificity of decoding, (2) the CCA-adding enzyme, which adds the CCA sequence to the tRNA 3' end to synthesize the mature tRNA, (3) aminoacyl-tRNA synthetases, which catalyze addition of an amino acid to each tRNA to synthesize the charged aminoacyl-tRNAs, and (4) the ribosome, which uses the charged aminoacyl-tRNAs as the substrates for protein synthesis.

To address these fundamental questions at the mechanistic level, we have developed a variety of methods, including biochemical, structural, kinetic, and genetic approaches. We focus on one representative enzyme in each case and build a framework of information by examining the enzyme in the larger biological context. Because tRNAs are ancient and enzymes that interact and recognize tRNAs are also ancient, we have a large database to search for related and homologous enzymes in evolution.

Our research provides the basis to gain biochemical, structural, and bioinformatic insights into tRNAs in evolution. These insights are important for understanding the origins of the genetic code and for developing new strategies for drug targeting against diseases arising from errors of tRNA functions.

Biochemistry; Biophysics; Developmental Biology; Genetics; transfer RNA; RNA modification; RNA repair; RNA maturation; Ribosome; Protein Synthesis; Antibiotics; Aminoacyl-tRNA Synthetase; Gene Expression; Bacterial Pathogenesis; Suppressor Mutation; Nucleic Acid Structure/Function; Pseudo-Complementary Nucleic Acid; Genetic Code; Protein Design

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