Research interests of Robert D. Wells, Ph.D. -- Unusual DNA structures and human hereditary neurological diseases

This laboratory is interested in the role of DNA structure in triplet repeat diseases. Recent investigations since 1991 have revealed that approximately 15 human hereditary neurological diseases are caused by the non-Mendelian expansion of simple triplet repeat sequences (CTGoCAG, CGGoCCG, and GAAoTTC). Some of these diseases are myotonic dystrophy, Huntington's disease, and Friedreich's ataxia. The clinical observation termed "anticipation" refers to the earlier age of onset and increased severity of the disease through a human pedigree. This non- Mendelian behavior is correlated with an increase in length of the triplet repeat sequences and is caused by the non-Mendelian expansion process. This laboratory is investigating the molecular mechanisms of the genetic instabilities that give rise to the disease etiology in well-defined genetic systems such as Escherichia coli. In addition, studies are underway on the DNA synthetic enzymes (polymerases and topoisomerases) that carry out the expansion process. DNA structural investigations have revealed the presence of a new, unusual conformation (flexible and writhed DNA) which is an intrinsic property of the CTGoCAG and CGGoCCG repeat sequences.

This laboratory has pioneered the investigations on non-B DNA structures at certain simple repeat sequences since 1966. While we have worked diligently to determine the biological role of these conformations, it has only recently been possible to demonstrate that triplexes, cruciforms, left-handed DNA, tetraplexes, etc., serve as the demarcation points for large genomic translocations; in turn, these translocations (deletions, inversions), cause at least 40 human diseases. Thus, the combined efforts of human genomics, medicine, DNA biochemistry, and molecular biology have provided exciting insights into the role of mutagenesis in genetic diseases.

Representative Publications

Wells, R. D. and Warren, S.T., eds. (1998) Genetic Instabilities and Hereditary Neurological Diseases. Academic Press Inc.

Long CTG Tracks From the Myotonic Dystrophy Gene Induce Deletions and Rearrangements During Recombination at the ARPT Locus in CHO Cells. James M. Meservy, R. Geoffrey Sargent, Ravi R. Iyer, Fung Chan, Gregory J. McKenzie, Robert D. Wells, and John H. Wilson. Molec. and Cellular Biol. 23, 3152-3162 (2003).

DNA Double-Strand Breaks Induce Instability of CTG•CAG Repeats Related to Hereditary Neurological Diseases in an Orientation-Dependent Manner in Escherichia coli. Micheal L. Hebert and Robert D. Wells. J. Mol. Biol. 336, 655-672 (2004).

Breakpoints of Gross Deletions Coincide with Non-B DNA Conformations. Albino Bacolla, Adam Jaworski, Jacquelynn E. Larson, John P. Jakupciak, Nadia Chuzhanova, Shaun S. Abeysinghe, Catherine D. O’Connell, David N. Cooper, and Robert D. Wells. Proc. Natl. Acad. Sci. 101, 14162-14167 (2004).

Non-B DNA Conformations, Genomic Rearrangements, and Genetic Diseases. Albino Bacolla and Robert D. Wells, Minireview. J. Biol. Chem. PIPS online on 08/23/04 (2004).

Transcription Influences the Types of Deletion and Expansion Products in an Orientation-Dependent Manner from GAC•GTC Repeats, a Triplet Repeat Associated with Skeletal Dysplasias. Liliana H. Mochmann and Robert D. Wells. Nucleic Acids Research 32, 4469-4479 (2004).

Hairpin Structure-Forming Propensity of the (CCTG•CAGG) Tetranucleotide Repeats Contributes to the Genetic Instability Associated with Myotonic Dystrophy Type 2. Ruhee Dere, Marek Napierala, Laura P.W. Ranum, and Robert D. Wells. J. Biol. Chem. 279, 41715-41726 (2004).