CHROMATIN GEOMETRY AND INTRACHANGE PROXIMITY EFFECTS

描述：尽管染色体是所有染色体中最大和最重要的 生物分子，人们对其大规模的了解相对较少 细胞周期间期的几何构型和运动。 辐射引起的染色体畸变，尤其是丰富的 用荧光原位杂交无法记分的像差 技术，是关于G0/G1期间染色体结构的信息，因为 不同像差类型的相对频率受以下因素影响 染色体的几何和运动。像差也强烈地牵涉到 放射生物学的所有医学方面，包括致癌、致死 肿瘤或周围正常组织中的细胞，并回顾 生物剂量学。尤其是交换型、染色体内染色体 异常(染色体互换，即倒位和环/缺失 事件)在所有这些原因下都很重要，但还不是很好 从实验和理论上都能理解，而不是其他像差 类型。场内很重要，特别是因为它们形成了很多 比基于基因组含量的随机性估计更频繁的是 预测。高频源于邻近效应，这增强了 如果两个DSB是成对的DSB非法重组的概率 最初形成的距离很近，如果两个DSB都打开，它们通常是这样 同样的染色体。例如，反转在癌症的发生中起着作用。 与易位相似，而且它们可能几乎与 易位，因为有如此多的小倒位；同样，小 基因缺失可能会致癌。这笔赠款将进行理论上和 计算机计算，与低空或低气压下的近距离效应有关 高LET到大规模间期染色质几何形状。最新聚合物 G0/G1期间大范围染色质构象模型将得到扩展 结合染色质系留和染色质运动。聚合物模型 导致对范围内尺寸谱的预测；例如估计 关于太小而不能用显微镜观察的长内波的频率 可以从观察到的臂内与臂间的比率中得出 内脏。机械计算机和生物物理模型的提出如下 一种相对便宜的方式来最大化可在上获得的信息 来自快速增长的像差数据库的染色质几何结构，以及 来帮助指导实验。

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.