CHROMATIN GEOMETRY AND INTRACHANGE PROXIMITY EFFECTS

描述：虽然染色体是最大、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，尤其是丰富的染色体畸变 使用荧光原位杂交无法评分的像差 技术，提供有关 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 染色体几何和运动。 像差也与 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，并回顾性 生物剂量测定。 特别是交换型、染色体内、染色体 畸变（染色体互换，即倒位和环/缺失 由于所有这些原因，事件）都很重要，但目前还不太好 与其他像差相比，实验和理论上都可以理解 类型。 内部变化很重要，尤其是因为它们形成得很多 比基于基因组内容的随机估计更频繁 预测。 高频源于邻近效应，这增强了 如果两个 DSB 是，则成对 DSB 非法重组的概率 最初形成紧密，如果两个 DSB 都打开，它们通常是这样的 同一条染色体。 例如，倒位在致癌过程中发挥作用 类似于易位，并且它们的频率可能几乎与 易位，因为有很多小的倒位；同样，小 缺失可能致癌。 该赠款将进行理论和 计算机计算，将邻近效应与低或低的内部变化相关 高 LET 到大规模间期染色质几何形状。 最近的聚合物 G0/G1 期间的大规模染色质构象模型将得到扩展 结合染色质束缚和染色质运动。 聚合物模型 导致对内部变化大小谱的预测；例如估计 内部变化的频率太小而无法在显微镜下观察到 可以从观察到的臂内与臂间的比率得出 内部变化。 机械计算机和生物物理建模被提出为 一种相对便宜的方式来最大化可获得的信息 来自快速增长的畸变数据库的染色质几何形状，以及 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.