Human Health: Faculty Research

Bioprocess, biomolecular and genetic engineering as related to human health

Richard R. Sinden:
DNA Structure and Function; therapeutic approaches to DNA structure associated genomic instability leading to disease 

• DNA structure and supercoiling
  The Sinden lab studies DNA, alternative conformation of DNA, and DNA supercoiling. Alternative conformations of DNA include cruciforms, left-handed Z-DNA, intramolecular triplex DNA, unwound DNA structures, and G-quadruplex structures. In 1995 we discovered a new alternative DNA structure called slipped-strand DNA. We have shown that many of these structures exist in the chromosomes of living bacterial cells. We work to understand the biological roles and consequences of these alternative DNA conformations in mammalian cells.
    
• Molecular mechanisms of spontaneous and genotoxicant-induced mutation
  A second area of research interest involves understanding the molecular mechanisms of mutagenesis. An exciting correlation exists between DNA sequences that form alternative structures and mutations that cause cancer and human genetic disease. That is – mutations do not really occur randomly, rather they are often templated by the DNA sequence itself. In other words, certain DNA sequences (DNA repeats) are their own worst enemy. These DNA sequences are prone to, or better perhaps, programmed for, self-directed mutation. We work to understand these molecular mechanisms of spontaneous mutagenesis that involve alternative DNA conformations. In addition, we have shown that many types of mutations occur preferentially on either the leading or lagging strand during replication. Currently, we are investigating the genetic instability of DNA sequences that form four-stranded, G-quadruplex structures. These sequences are associated with genetic instabilities associated with cancer.
    
• DNA repeat and genomic instabilities associated with human genetic neurodegenerative disease
  A third area of interest involves understanding the molecular basis of certain human genetic diseases, including Huntington disease, myotonic dystrophies, fragile X syndrome, spinocerebellar ataxias, and Friedreich ataxia. This area of research integrates the above two focus areas: DNA structure and spontaneous mutagenesis. Currently, more than 40 human genetic neurodegenerative diseases are caused by the massive expansion of (CTG)n•(CAG)n, (CGG)n•(CCG)n, (GAA)n•(TTC)n, (CCTG)n•(CAGG)n, or (ATTCT)n•(AGAAT)n DNA repeats. All these DNA repeats form one or more alternative DNA conformations, including hairpins, slipped strand DNA, parallel DNA, triplex DNA, and unwound structures, which are likely involved in their genomic instability (i.e., expansion or deletion mutations). We have developed genetic assays for studying the deletion of DNA repeats in a model bacterial system. A goal of our laboratory is to understand the molecular basis for the expansion (and deletion) mutations and to find a therapeutic approach for reducing repeat length.
  
  We are currently investigating the role of tryptanthrins and coralyne derivatives as chemicals that may stabilize intramolecular triplex DNA and lead to increased rates of deletion of the Friedreich Ataxia (GAA)n•(TTC)n repeats. With such an approach, one may be able to prevent or delay onset of repeat expansion diseases.