Weiss Lab Research

Sexual dimorphism provides an example of a genetic switch in the pattern of development. Although upstream mechanisms of sex determination differ among phyla, a universal male-determining element is proposed in the downstream pathway, encoded by the newly recognized DM motif. The DNA-binding motif is conserved among the sex-determining hierarchies of the fruit fly (Doublesex in Drosophila melanogaster) and worm (MAB-3 in C. elegans). DM genes also occur in vertebrate genomes. Remarkably, two are encoded in human chromosome 9 at a site in which deletions or translocations cause XY sex reversal (46, XY gonadal dysgenesis). The DM motif binds zinc and represents a novel Zn-binding module.

Our studies focus on the structure and function of the DM DNA-binding domain. A combination of biochemical, spectroscopic and crystallographic methods are being applied to elucidate its structure and mechanism of DNA recognition. Particular emphasis is placed on roles of amino-acid residues at sites of mutation associated with intersex phenotypes in the fly and worm. Future studies will seek to define downstream target genes exploiting the availability of genome sequences.

Selected Publications:

Benevides, J.M., Li, T., Lu, X.J., Srinivasan. A.R., Olson, W.K., Weiss, M.A., and Thomas Jr., G.J.,
"Protein-Directed DNA Structure II. Raman Spectroscopy of a Leucine Zipper bZIP Complex."
Biochemistry (2000) 39:548-556
Benevides, J.M., Chan, G., Lu, X.J., Olson, W.K., Weiss, M.A., and Thomas Jr., G.J.,
"Protein-Directed DNA Structure I. Raman Spectroscopy of a High-Mobility-Group Box with Application toHuman Sex Reversal."
Biochemistry (2000) 39:537-547
Weiss, M. A., and King, C.-Y.
"Imino Proton Exchange Provides an 1H-NMR Footprint of Protein-DNA Interactions: General Strategy and Application to the SRY HMG box."
J. Biomolec. Struc. Dynamics (1995) 13(2):261-8.
Peters, R., King, C.-Y., Ukiyama, E., Falsafi, S., Donahoe, P. K. and Weiss, M. A.
"An SRY Mutation Causing Human Sex Reversal Resolves a General Mechanism of Structure-Specific DNA Recognition: Application to the Four-Way DNA Junction."
Biochemistry (1994) 34:4569-4576.
Haqq, C. M., King, C.-Y., Ukiyama, E., Haqq, T. N., Falsalfi, S., Donahoe, P. K., and Weiss, M. A.
"Molecular Basis of Mammalian Sexual Determination: Activation of MIS by SRY."
Science (1994) 266:1494-1500
King, C.-Y. and Weiss, M. A.
"The SRY HMG-Box Recognizes DNA by Partial Intercalation in the Minor Groove: a Topological Mechanism of Sequence Specificity."
Proc. Natl. Acad. Sci. U.S.A. (1993) 90:11990-11994