Molecular Biology

Chairman's Overview

Peter E. Wright, Ph.D.

Molecular biology forms the cornerstone of biological and biomedical research. Research in the Department of Molecular Biology encompasses a broad range of disciplines, extending from structural and computational biology at one extreme to molecular genetics at the other. Our scientists continue to make rapid progress toward a deeper understanding of the fundamental molecular events that underlie the processes of life. Major advances have been made in elucidating the structural biology of signal transduction, receptor recognition, and viral assembly; understanding mechanisms of viral infectivity; determining the structures of membrane proteins and multidrug transporters; understanding the molecular basis of nucleic acid recognition and DNA repair; and determining the mechanisms of protein folding and ribosome assembly.

Progress has been made in elucidating the molecular events involved in regulation of the cell cycle, tumor development, induction of sleep, the molecular origins of neuronal development and of CNS disorders, the regulation of transcription, and decoding of genetic information in translation. Finally, new advances have been made in the design of novel low molecular weight compounds that can specifically regulate genes and in biomolecular engineering, building novel functions into viruses, antibodies, zinc finger proteins, RNA, and DNA. Progress in these and other areas is described in detail on the following pages, and only a few highlights are mentioned here.

In a landmark achievement, ranked as 1 of the top 10 breakthroughs of 2007 by Science magazine, Raymond Stevens and his collaborators determined the 3- dimensional structure of the β₂-adrenergic receptor. This structure, which represents the culmination of 15 years of research in the Stevens laboratory, promises to revolutionize research on G protein—coupled receptors (GPCRs) and have a major impact on drug discovery. More than 800 GPCRs have been identified, making them the largest family of membrane protein receptors, yet previously, the structure of only 1 GPCR was available, for the light receptor rhodopsin. The structure of the β₂-adrenergic receptor provides the first insights into the large class of GPCRs that regulate signal transduction processes by binding diffusible ligands. The GPCRs control a broad spectrum of physiologic responses, activating intracellular signaling pathways in response to stimuli from outside the cell. GPCRs regulate cell growth and differentiation; control cardiovascular function, metabolism, and the immune response; and play a key role in neurotransmission. Approximately half of currently used drugs function by binding to and regulating receptors from the GPCR family. The structure of the β₂-adrenergic receptor provides unprecedented insights into the mechanism by which GPCRs interact with their natural ligands and with drugs and paves the way to design of new and more effective pharmaceutical agents with fewer side effects.

Research in the laboratory of John Tainer has led to a detailed understanding of the mechanism by which mutations in a critical enzyme involved in DNA repair lead to 3 distinct disease phenotypes. Dr. Tainer and coworkers determined the structure of the XPD helicase, which is absolutely required for nucleotide excision repair of damaged DNA, and measured the effects of disease-causing mutations on the enzymatic activity of the helicase. Mutations associated with xeroderma pigmentosum impair the DNA helicase activity of XPD and greatly predispose patients to skin cancer. Mutations associated with Cockayne syndrome also reduce helicase activity and, in addition, cause the XPD enzyme to become stuck on the DNA that is undergoing repair. Finally, trichothiodystrophy mutants cause framework defects that disrupt the integrity of the repair machinery. Related structural work in the Tainer laboratory provided important insights into the mechanism of base excision repair of damaged DNA. A molecular level knowledge of mechanisms of DNA repair is of central importance to understanding cancer, developmental diseases, and aging, and pathogen-specific DNA repair enzymes are potential targets for novel antibacterial and antifungal agents.

A collaboration between Curt Wittenberg and Paul Russell of our department and John Yates, Department of Cell Biology, has led to novel insights into the molecular mechanism by which cells respond to errors in DNA replication. During normal cell division, a protein named Nrm1 binds to DNA and represses the expression of key genes during the G₁ phase of the cell cycle. Under conditions of stress, replication stalls, and repression of these G₁-phase genes by Nrm1 is blocked, resulting in expression of proteins needed to correct the problem that caused the stall. Understanding the molecular mechanisms responsible for checkpoint control during the cell cycle is critical for understanding oncogenesis and may eventually facilitate development of novel cancer therapeutics that target the replication checkpoints.

Recent work by Paul Schimmel and members of his group has revealed the mechanism by which alanyl-tRNA synthetase edits mischarged tRNA^Ala to correct errors of protein synthesis. Mistranslation, which occurs when an incorrect amino acid binds to tRNA and becomes incorporated into a protein, leads to synthesis of proteins containing errors. Such errors of protein synthesis are associated with numerous diseases. The research by Dr. Schimmel and coworkers provides novel insights into the checkpoints that guard against misincorporation of amino acids and greatly extends our understanding of how cells avoid errors during protein synthesis.

Research by Nick Boddy, Clare McGowan, John Tainer, and their coworkers has led to the identification of a previously unknown and completely unexpected family of ubiquitin ligases that mediate cross talk between the sumoylation and ubiquitination pathways. These SUMO-targeted ubiquitin ligases specifically target SUMO-modified proteins for ubiquitination and subsequent proteasomal degradation. The ligases bind specifically to sumoylated proteins and catalyze ubiquitination of the proteins, thereby playing a central role in regulation of sumoylation pathways and in the homeostasis of SUMO-
modified proteins. SUMO-targeted ubiquitin ligases are involved in the regulation of genome stability, and evidence exists that they play a central role in controlling cancer metastasis, making them potential targets for novel therapeutics designed to inhibit cancer growth.

Molecular biology remains a field of enormous opportunity and excitement. The scientists in this department are taking full advantage of powerful new technologies to advance our understanding of fundamental biological processes at the molecular level. Their discoveries will ultimately be translated into new advances in biotechnology and medicine.