If pathways that have been previously identified to modulate rDNA recombination do not adequately account for the age-associated increase in LOH rates, can this phenotype be a response to a change in a more general biological process that is most readily manifested at the rDNA? Since DSBs within the rDNA array normally arise through the interaction between DNA replication forks and Fob1 [57], we speculate that DSB rates in the rDNA are modulated by DNA replication stress. This model is supported by several lines of evidence: A hypomorphic allele of the essential DNA replication helicase encoded by DNA2 results in an increased frequency of DSBs within the rDNA, which can be suppressed by deletion of FOB1 [57]–[58]. Similarly, mutations in DNA polymerase α and δ subunits can also lead to increased DSBs within the rDNA array [26], [59]. Deletion of RRM3, a helicase that functions to remove non-histone protein barriers from DNA, also affects rDNA recombination [60]–[61]. Further evidence comes from a screen for deletion mutants that increase LOH in young cells [17], which classified mutations based on locus specificity,
