Balancing DNA Pathways

Neurological disorders such as Fragile X syndrome and Huntington's disease are caused by abnormally long repetitions of DNA triplet sequences, and this type of genomic expansion can be induced by DNA repair. A team led by Rutgers University chemist Kenneth J. Breslauer has now found an explanation for how this unfortunate coupling may occur (J. Am. Chem. Soc., DOI: 10.1021/ja902161e).

"It's the ultimate example of a cruel trick by nature," Breslauer says. "Sometimes doing good by repairing DNA damage can unwittingly result in evil through inducing DNA expansion."

The team created oligonucleotide constructs containing an abasic site, the universal intermediate in DNA repair where a damaged base has been removed, in close proximity to a bulge loop structure with triplet repeats, which is essential to DNA expansion. And they found that the abasic site increases the relative stability of the bulge loop structure, enabling DNA expansion.

The presence of an abasic site impacts proximal DNA domains, much like a wave propagating through water, Breslauer says. But preventing DNA repeat expansion is not as simple as downregulating DNA repair, he adds. "If you inhibit DNA repair to limit DNA-expansion diseases, then what you've done is increase the risk of mutagenesis and cancer."

"The insights provided by this study should help us understand the delicate balance between pathways needed to maximize the positive influences of DNA repair, while minimizing the negative impact of excessive DNA triplet-repeat expansion," says University of Michigan DNA expert Gary Glick. "Such mechanistic insights are required for the rational design of diagnostic and therapeutic protocols."

Samuel H. Wilson, a principal investigator at the National Institute of Environmental Health Sciences, in Research Triangle Park, N.C., who helped discover the link between DNA repair and triplet-repeat expansion, calls the findings "incredibly important." But he notes that there are probably multiple pathways involved in DNA expansion and that this paper should stimulate much more research in the field.