BRENDA L. BASS
Brenda Bass
email: bbass@biochem.utah.edu		 Distinguished Professor of Biochemistry
Adjunct Professor of Human Genetics

The Bass Lab
Molecular Neuroscience
Brain and Behavior

B.A. 1977, Colorado College; Ph.D. 1985, University of Colorado; Postdoctoral Fellow, 1985-89, Fred Hutchison Cancer Center, Seattle Washington.

RESEARCH:

Determining the roles of RNA editing in the nervous system, using C. elegans as a model system.

Research in my laboratory is focused on double-stranded RNA (dsRNA)--its biologic functions and the proteins that bind it to mediate these functions. Our studies are divided between two dsRNA-mediated pathways: RNA editing by adenosine deaminases that act on RNA (ADARs), and RNA interference (RNAi). For both pathways we perform in vitro studies to answer mechanistic questions, and in vivo studies in C. elegans to understand biologic function. dsRNA binding proteins (dsRBPs) bind tightly to dsRNA of any sequence, and a dsRNA substrate for one dsRBP is also a substrate for others. This suggests that different dsRNA-mediated pathways intersect and affect each other, and thus, we also study how RNA editing affects RNAi.

ADARs deaminate adenosines in double-stranded regions of cellular and viral RNAs to create the nucleoside inosine. Inosine is read as guanosine by the translational machinery, and one function of ADARs is to deaminate adenosines within codons, so that multiple protein isoforms can be synthesized from a single, encoded mRNA. In this way ADARs create protein isoforms of hepatitis delta antigen, and many proteins involved in neurotransmission, such as serotonin receptors and glutamate receptors. Consistent with the observation that ADARs are highly expressed in the nervous system, mutant animals lacking ADARs have behavioral defects. For example, our characterizations of C. elegans strains lacking ADARs show that these animals have aberrant chemotaxis and thermotaxis behaviors.

Several years ago my laboratory developed a method to identify inosine-containing RNA, and applied the method to mRNA isolated from C. elegans and human brain. We found inosines in remarkably stable structures that sometimes contain hundreds of nearly contiguous base-pairs. Surprisingly, the edited structures were in non-coding regions of mRNAs, such as 5' and 3' untranslated regions (UTRs), and introns. Our data suggest non-coding sequences are the primary targets of ADARs and that ADARs have functions in addition to altering codon meaning. Researchers in my lab are attempting to understand the function of these long double-stranded structures and the inosines within them. One possibility is that the structures induce silencing via the RNAi pathway, and that editing regulates this silencing. In support of this idea, we find that behavioral defects of C. elegans strains lacking ADARs can be rescued by a second mutation in a gene required for RNAi.

Recently, in collaboration with the Hill lab, we solved the crystal structure of the catalytic domain of human ADAR2. This study shows that ADAR catalysis involves a catalytic zinc coordinated to two cysteines and a histidine, as predicted from sequence similarities to the cytidine deaminase family. Future biochemical studies will focus on testing hypotheses about mechanism, substrate recognition, and substrate specificity that are suggested by the structure.

In addition to our studies on how RNA editing affects RNAi, we are also interested in the RNAi pathway in its own right, in particular, as it occurs in C. elegans. Biochemical studies are focused on the dsRBPs required for RNAi in C. elegans, and we analyze their RNA binding properties and their catalytic activities in vitro. In regard to biologic function we want to understand the natural roles of dsRNA-mediated gene silencing. We are using microarray analyses to identify genes that are misregulated in C. elegans strains containing mutations in the Dicer gene, as well as those with mutations in other genes required for RNAi.

Selected Publications

Welker, N.C., Habig, J.W., Bass, B.L. (2007) Genes misregulated in C. elegans deficient in Dicer, RDE-4, or RDE-1, are enriched for innate immunity genes. RNA, 13:1090-1102.

Parker, G.S., Eckert, D.M., Bass, B.L. (2006) RDE-4 preferentially binds long dsRNA and its dimerization is necessary for cleavage of dsRNA to siRNA. RNA, 12:807-818.

Haudenschild, B.L., Maydanovych, O., Véliz, E.A., Macbeth, M.R., Bass, B.L., and Beal, P.A. (2004) A Transition State Analog for an RNA-editing Reaction. J. Am. Chem. Soc., 126:11213-11219.

Macbeth, M.R., Lingam, A.T., and Bass, B.L. (2004) Evidence for auto-inhibition by the N-terminus of hADAR2 and activation by dsRNA binding. RNA, 10:1563-1571.

Tonkin, L.A., and Bass, B.L. (2003) Mutations in RNAi rescue aberrant chemotaxis of ADAR mutants. Science, 302:1725.

Tonkin, L.A., Saccomanno, L., Morse, D.P., Brodigan, T., Krause, M., and Bass, B. (2002) RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. Embo Journal, 21:6025-6035.

Knight, S.W., and Bass, B.L. (2002) The role of RNA editing by ADARs in RNAi. Molecular Cell, 10:809-817.

Morse, D.P., Aruscavage, P.J., and Bass, B.L. (2002) RNA hairpins in noncoding regions of human brain and Caenorhabditis elegans mRNA are edited by adenosine deaminases that act on RNA. Proc. Natl. Acad. Sci. USA 99:7906-7911.

Knight, S.W., and Bass, B.L. (2001) A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in C. elegans. Science 293:2269-2271.

Lehmann, K.A., and Bass, B.L. (2000) Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. Biochemistry 39:12875-12884.

Domeier, M.E., Morse, D.P. Knight, S.W., Portereiko, M., Bass, B.L., and Mango, S.E. (2000) A link between RNA interference and nonsense-mediated decay in Caenorhabditis elegans. Science 289:1928-1930.

Bass, B.L. (2000) Double-stranded RNA as a template for gene silencing. Cell 101:235-238.

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