( somal DNA typically small loops of rep...)Regulating the nuclear architecture of the cell

When the H3K9 methylation pathway is functioning properly, heterochromatin remains condensed and a single nucleolus forms around the ribosomal DNA. But lack of H3K9 methylation -- whether from a mutation in Su(var)3-9; or in the gene that codes for the HP1 protein; or a mutation that disables RNA interference -- allows the heterochromatin to open up. The decondensed, repeated DNAs are then free to interact; DNA recombination and repair processes excise the DNA from the chromosome to form extrachromosomal DNA. If these extrachromosomal loops consist of ribosomal DNA, they further accelerate the production of misplaced nucleoli.

Curiously, says Karpen, this chaotic state of affairs is not, by itself, fatal to the organism. "I wondered why the flies with mutations in these important pathways didn't die. But replication and cell division checkpoints slow down the cell cycle when damaged DNA is detected, and DNA repair mechanisms move in to fix the damage." However, if these replication checkpoints are crippled in flies that also have mutations in the H3K9 methylation and RNAi pathways, Karpen says, genome aberrations accumulate "and they do die."

Says Karpen, "These findings have broad implications for genome stability. We plan to investigate whether the H3K9 and RNAi pathways we've identified in Drosophila play the same role in humans; if so, misregulation of heterochromatin could be one cause of the rampant genome instability observed in cancer. Beyond these specific pathways, we're interested in the larger question of how such pathways affect the organization of the chromosomes in the cell nucleus."
'"/>

Source:DOE/Lawrence Berkeley National Laboratory