Retrotransposons Drive Genome Instability in Aging Cells

Genome instability is a ubiquitous property of aging and malignant cells. Our labs study the role of retrotransposons in driving genome instability, using the Ty1 long terminal repeat‐retrotransposon in Saccharomyces cerevisiae as a model. Ty1 reverse transcriptase (RT) activity is stimulated by S‐phase checkpoint pathways, which are activated by a variety of DNA lesions, including telomerase erosion. Damage‐induced Ty1 RT activity leads to retrotransposition and the formation of chimeric retrotranscripts derived from Ty1 and other cellular mRNAs. Chimeric retrotranscripts repair chromosomal breaks and elongate eroding telomeres, forming genome rearrangements in the process. Recent studies indicate that formation of genomic retrotranscripts is elevated in old yeast populations and that new retrotranscripts are beacons of chromosomal rearrangements in old cells. Moreover, the increases in loss of heterozygosity and chromosome loss that are characteristic of aging populations were significantly diminished when Ty1 RT activity was blocked by a variety of mutations and inhibitors. Our findings suggest that retrotranscript‐mediated genome rearrangements are integral to aging‐related genome instability.