The long-term goal of this work is to understand how gene silencing mechanisms regulate the stability of the highly repetitive ribosomal RNA (rRNA) genes. The stability of this locus is crucial for growth and survival and its highly repetitive nature presents an opportunity to explore the mechanisms that stabilize DNA repeats against homologous recombination. We have identified the silencing complexes that regulate rDNA recombination. The molecular composition of these complexes suggests a new mechanism for how homologous recombination within repetitive DMA regions can be curtailed. The mechanism is likely to involve the bridging of sister DNA chromatids after DMA replication by a clamp complex, termed the cohibin complex, that prevents DNA repeats from sliding relative to each other. This clamping inhibits inappropriate recombination events between out of reguster repeat units. A second set of proteins is localized to the inner nuclear envelop and physically interacts with cohibin. These membrane proteins may tether rRNA genes to the nuclear periphery. This tethering is proposed to provide a second safeguard against inappropriate recombination. Repeated DNA sequences form the largest portion of the genomes of complex eukaryotes such as humans. Repeat instability is associated with general chromosome instability in cancers and other diseases. A basic understanding of the mechanisms that ensure the stability of DNA repeats in yeast will also increase our understanding of repeat and chromosome stability in human cells and may lead to the design of better preventative and therapeutic strategies that deal with diseases of chromosome stability.
|Mekhail, Karim; Seebacher, Jan; Gygi, Steven P et al. (2008) Role for perinuclear chromosome tethering in maintenance of genome stability. Nature 456:667-70|