MOLECULAR AND GENETIC ANALYSIS OF CHROMATIN STRUCTURE

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The very large genomes of higher eukaryotes must be condensed into a relatively small volume inside the nucleus. This is accomplished by assembling the DNA into a complex multi-level nucleoprotein structure, chromatin. The first level of organization is the beads-on-a string array of nucleosome core particles. In the second level this array is coiled into a 30 nM fiber, while in the third level, 30 nM fiber is thought to be segregated into a series of topologically independent domains. While these three different levels of chromatin organization provide a mechanism for compacting eukaryotic chromosomes more than two orders of magnitude over B-form DNA, it is important to remember that this nucleoprotein complex must at the same time be used as the substrate for replication, recombination, and transcription. That the packaging of the DNA into chromatin poses a significant impediment to these processes is amply demonstrated by both genetic and biochemical studies which have shown that nucleosomes and histone HI function as quite potent general repressors of transcription. Consequently, it must be supposed that at each level of chromatin organization the DNA is condensed in a manner which leaves key sequences readily accessible to the enzymes involved in these processes. Moreover, there must also be mechanisms that facilitate rapid transitions from one level of chromatin compaction to another in order accommodate the alterations in the topology of DNA that are induced by transcription, replication and perhaps even recombination. It is the balancing of these conflicting demands---those required for the tight compaction of the chromosome versus those required for the ready utilization and propagation of genetic information-- that is the subject of this application.