The first analyses of the human genome project draft sequence were recently
published. What has been made clear from these adventuresome projects is
how little we know about the human genome. It is comprised of approximately
3 billion base pairs. Of that total, only about 3% is accounted for by
protein-coding regions. The remaining 97% of the human genome encodes no
proteins, and has been referred to as "junk" DNA. However, this
term is misleading, as these regions may play vital roles in normal genome
structure, organization, plasticity and function. Much of this non-coding
DNA consists of highly repetitive segments. One such class of sequences
in humans consists of simple tandem repeats (STRs), also known as microsatellite
DNA.
Microsatellites are ubiquitous short tandem-repeat sequences widely and randomly distributed throughout eukaryotic genomes. They are acutely prone to replication errors that result in expansions and contractions of repeat unit (repeat length variability) because of misalignment of the template and daughter strands. A number of human genes contain microsatellite repeats within the coding and non-coding regions of the transcribed sequences. It has been suggested that instability of repeat sequences in the coding regions of several of these genes, plays a role in the function of these genes, presumably by gene inactivation through the introduction of frameshift mutations. Variability of microsatellite repeat lengths in non-coding regions of transcripts has also been implicated in the regulation of gene expression.
Genomic instability is a molecular feature common to the progression of many cancers, particularly those that demonstrate defects in DNA mismatch repair (MMR) enzymes. The primary role of the MMR system is to maintain genomic stability by removing replication errors from DNA. This repair pathway was originally implicated in human cancer through an association between microsatellite instability (MSI) in colorectal tumors of hereditary nonpolyposis colon cancer (HNPCC). A number of human genes associated with cancer contain microsatellite repeats within the coding and non-coding regions of the transcribed sequences. It has been suggested that instability of repeat sequences in the coding regions of several of these genes, plays a role in the progression of disease, presumably by gene inactivation through the introduction of frameshift mutations. Variability of microsatellite repeat lengths in non-coding regions of transcripts has also been implicated in the regulation of gene expression (when and how a gene is turned on or turned off).
The hypothesis of this proposal is that the genes in the molecular pathway(s) of cancer progression are subject to gene regulation by microsatellite repeat sequence variability, and that the accumulation of these variants through defects in MMR contribute to cancer progression. The completion of the human genome sequence offers the opportunity to screen for and evaluate the role of these simple sequence repeats in genome maintenance and gene expression. The aims of this study are to (1) identify coding and non-coding repeat sequences in genes implicated in the genetics of cancer, (2) evaluate and correlate repeat variability with cancer-associated changes and (3) assay gene expression and activity levels in genes demonstrating microsatellite variability.
The results of these studies should contribute to our current understanding of cancer, identify molecular markers of cancer progression and perhaps shed light on atypical modulators of gene expression.
Click here to see a model of Strand Slippage (pdf file-need adobe reader)
Home || Cancer research || Deafness
Research || Course Information
Curriculum Vitae || Publications & Abstracts
Dept.
Bio&Env. Sci. Home || U. Tenn. at Chattanooga
Home