CHROMATIN GEOMETRY AND INTRACHANGE PROXIMITY EFFECTS

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DESCRIPTION: Although chromosomes are the largest and most important of all biomolecules, comparatively little is known about their large-scale geometric configurations and motions during cell cycle interphase. Radiation-produced chromosome aberrations, especially the rich variety of aberrations that can no be scored using fluorescent in situ hybridization techniques, are informative about chromosome structure during G0/G1, because the relative frequency of different aberration types is influenced by chromosome geometry and motion. Aberrations are also robustly implicated in all the medical aspects of radiobiology, including carcinogenesis, killing of cells in tumors or surrounding normal tissues, and retrospective biodosimetry. In particular, exchange-type, intrachromosomal, chromosome aberrations (chromosome interchanges, i.e., inversions and ring/deletion events) are important for all these reason, but are as yet less well understood, experimentally and theoretically, than are other aberration types. Intrachanges are important especially because they are formed much more frequently than randomness estimates based on genomic content would predict. The high frequency stems fro proximity effects, which enhance the probability of pairwise DSB illegitimate recombination if the two DSBs are initially formed close together, as they typically are if both DSBs are on the same chromosome. For example, inversions play a role in carcinogenesis similar to that of translocations, and they may be almost as frequent as translocations because there are so many small inversions; similarly, small deletions can be carcinogenic. The grant will undertake theoretical and computer calculations, relating proximity effects fo intrachanges at low or high LET to large-scale interphase chromatin geometry. Recent polymer models of large-scale chromatin conformation during G0/G1 will be extended to incorporate chromatin tethering and chromatin motion. The polymer models lead to predictions on the intrachange size spectrum; for example estimates on the frequency of intrachanges too small to be observed microscopically can be derived from the observed ratio of intra-arm to inter-arm intrachanges. Mechanistic computer and biophysical modeling is proposed as a comparatively inexpensive way to maximize information obtainable on chromatin geometry from the rapidly increasing database on aberrations, and to help guide experiments.