While the effects of DNA replication stress on the rDNA may be dependent on Fob1, the mode of action may not necessarily be specific to the rDNA. Ivessa, et al. identified genomic regions prone to DNA replication fork pausing in an rrm3Δ mutant which included centromeric regions, tRNAs and sub-telomeric sequences in addition to the rDNA array [9]. Similarly, RRM3 was originally identified in a genetic screen for mutations that induce gene duplication at the tandemly repeated CUP1 locus [60], which suggests that other regions of the genome that combine replication fork blocks with repetitive sequence elements could also generate age-associated LOH events. While repetitive elements are uncommon in the S. cerevisiae genome, the ubiquitous nature of these features in mammalian genomes suggests great potential for age-associated genomic instability generated by a similar mechanism.
