Researchers in the School of Biology at Georgia Tech have uncovered a novel mechanism of genome mutagenesis and remodeling that could help to explain abnormal DNA amplification in cancer and other degenerative disorders. Cancer and other degenerative disorders are commonly associated with abnormal DNA amplification (resulting in an increase in the number of copies of a DNA segment) in various locations throughout the genome. These mutations can facilitate the aggressiveness of cancer to the detriment of human health and are therefore of great scientific interest. Kuntal Mukherjee, former postdoctoral fellow in the lab of Francesca Storici, developed an approach to capture the events of DNA amplification driven by small pieces of DNA in yeast cells and provided initial characterization of the mechanism. The discovery, published this week in PLoS Genetics (http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003119), reveals that small pieces of DNA can be potent inducers of gene amplification and genomic rearrangement.

Small DNA fragments can form as byproducts of DNA metabolism, reverse transcription or DNA degradation. In addition after cells lyse, or undergo apoptosis, these fragments (or DNA debris) can be released into extracellular space and taken up by neighboring cells. Due to complementarity, the small DNA fragments can direct specific amplification events in homologous chromosomal regions, resulting in Small Fragment-driven DNA Amplification (SFDA). Mukherjee and Storici demonstrate that SFDA results in tandem chromosomal duplications or formation of extrachromosomal circles that mimic the DNA amplification structures commonly found in many cancer cells. Prominent examples of these mutations in cancer include the repeated units clustered at a single chromosomal locus (homogeneously staining regions) and the circular extrachromosomal elements replicating autonomously and lacking a centromere and telomeres (double minutes).

The implications of their discovery suggest that DNA debris could potentially spread chromosomal rearrangements from one cell to another like ‘infectious’ agents. Considering that DNA fragments are highly recombinogenic and also highly abundant in cells, the researchers propose that SFDA could be a common mechanism of DNA amplification-driven carcinogenesis, as well as a more general cause of DNA copy number variation in nature.

This project was supported by the Georgia Cancer Coalition grant (award R9028).