Why might reduced Sir2 protein levels in aging cells fail to alter rDNA recombination rates in a fashion similar to young cells? One possible explanation is a phenotypic lag of the increased rDNA recombination that lasts for >10 generations after the reduction of Sir2 protein. For instance, if Sir2 is completely absent in most cells, then one of it substrates (e.g. K16 of histone H4) may not immediately become acetylated [52]. In fact, newly synthesized histones start out in an unacetylated state, and how a heritable switch between acetylated and unacetylated states of histones occurs remains mysterious [53]. Another possibility is that a very low level of Sir2 protein may be sufficient to suppress rDNA recombination. Relevant to this idea, different regions of silent chromatin can compete for recruitment of Sir2 [37], [54]. If the rDNA array is dominant in such a competition, the effect of declining Sir2 levels could be masked.
