2008 Tenovus-Scotland Medal Lecture
Prof Darren Monckton, University of Glasgow
Unstable DNA and human disease: when DNA repair goes bad
The genetic material, DNA, contains all of the information necessary to build an entire human being, but even one mistake in the six billion bases of DNA that are passed on from one generation to the next can cause devastating inherited disease. Fortunately, millions of years of natural selection has resulted in the evolution of multiple DNA repair systems that act to ensure that DNA is faithfully copied from one cell to the next and from generation to generation, and maintained intact throughout the lifetime of the individual. Thus, DNA is usually accurately transmitted from one generation to the next and disease causing new mutations are usually very rare. However, this paradigm has been shattered by the discovery of the molecular basis of a group of disorders, including myotonic dystrophy and Huntington disease, that share features of wide symptomatic variabilityand bizarre inheritance patterns. In these disorders, a simple sequence repeat within the gene expands beyond the range usually observed in the general population. Longer repeat tracts are associated with more severe symptoms and an earlier age of onset. Once into the disease associated range, the DNA simple sequence repeats become dramatically unstable and nearly always increases in length when transmitted from one generation to the next. Hence, the symptoms are more severe and appear earlier in successive generations, a phenomenon termed anticipation.
It has also become apparent that expanded repeat tracts are also highly unstable in the somatic tissues of the body in a process that is age-dependent, tissue-specific and highly expansion-biased, properties that contribute toward both the tissue-specificity and progressive nature of the symptoms. Contrary to expectations, these mutations do not occur when the DNA is being copied from one cell to another. Even more unexpectedly, the process of repeat expansion actually requires the activity of DNA mismatch repair enzymes; proteins whose normal function is to prevent the accumulation of mutations. In addition to these trans-acting genetic modifiers, it is also apparent that repeat expansion is subject to major genomic position effects. The precise nature of these cis-acting modifiers has proven more elusive, but it is clear that there is a strong correlation with instability and the GC content of the flanking DNA, with recent data suggesting that epigenetic modifications may also be critical. In addition to the exciting insights into DNA metabolism that these data reveal, they also suggest the genetic instability underlying these disease might be a direct target for therapeutic intervention. Indeed, we have already demonstrated that it is possible to slow the rate expansion using small molecule drugs. Slowing the rate of expansion is expected to be therapeutically beneficial, but our long term aim remains the induction of the contractions that we predict to be curative.
Also see: Tomorrow Belongs to Me A collaboration between artist Jacqueline Donachie and Darren Monckton on anticipation and the progression of genetically inherited diseases