Adam Bailis, Ph.D. Research

Genome Instability Associated With Aging and Radiation Exposure
 
Genome instability in the form of mutations, loss of heterozygosity (LOH), and chromosomal rearrangements contributes to tumorigenesis. These genetic changes result from exposure to endogenous and exogenous sources of DNA damage, ranging from spontaneous DNA replication failure and oxidative metabolism, to toxic chemicals, and radiation. A broad array of DNA repair functions in cells address this damage and attenuate genome instability. Therefore, both increased DNA damage and decreased DNA repair enhance genome instability and increase the incidence of cancer.
 
As we age, we experience a cumulative increase in DNA damage. For example, cells in many tissues progressively lose the ends of their chromosomes, or telomeres, due to the absence of telomerase, an enzyme required for telomere replication. As telomeres erode they facilitate genome destabilization, and elicit cellular senescence. Using Saccharomyces cerevisiae, a model eukaryotic system, we have found that telomerase-defective cells exhibit increased mutagenesis, LOH, and genome rearrangements as the cells approach senescence. Importantly, these senescence-dependent responses appear to involve the same DNA repair factors that generate genome instability in response to DNA replication failure. This suggests that senescence-associated genome instability is the product of increased DNA replication failure in senescent cells. Similar increases in senescence-associated genome instability in the elderly may contribute to the increased incidence of cancer after the fifth decade of life.
 
Acute doses of radiation acquired through accidental or treatment related exposure have been shown to increase both genome rearrangement and cancer in humans. In particular, translocations, rearrangements of segments of the same or different chromosomes have been observed in thyroid carcinomas and lymphomas arising from irradiation. DNA double-strand breaks (DSBs) are the most problematic result of radiation exposure and are known to greatly stimulate genome rearrangement. We have created a model of acute radiation exposure by simultaneously generating DSBs on two chromosomes, which enormously stimulates translocation formation. The involvement of a suite of important DNA repair factors suggests that the translocations evolve from the annealing of homologous sequences at the broken ends of the chromosomes. Given the broad distribution of highly repetitive sequences in the human genome, this process is very likely to generate translocations following acute radiation exposure, and could be a major source of the genome instability and cancer that follows.