CHROMATIN GEOMETRY AND INTRACHANGE PROXIMITY EFFECTS

染色质几何结构和变化内邻近效应

• 批准号: 2910389
• 负责人: RAINER K SACHS
• 金额: $ 16.9万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2910389
• 关键词: DNA damage; apoptosis; cell cycle; chromatin; chromosome aberrations; chromosome walking; computer simulation; conformation; gene frequency; genetic recombination; mathematical model; mutant; polymers; radiation dosage; radiation genetics

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.

描述：虽然染色体是最大和最重要的所有 生物分子，相对而言，对它们的大规模 细胞周期间期的几何构型和运动。 辐射引起的染色体畸变，特别是各种各样的 不能用荧光原位杂交评分的畸变 技术，是关于染色体结构在G 0/G1，因为 不同像差类型的相对频率受到以下因素的影响 染色体的几何形状和运动。 畸变也强烈地涉及到 放射生物学的所有医学方面，包括致癌作用， 肿瘤或周围正常组织中的细胞， 生物剂量学 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 事件）对于所有这些原因都是重要的，但还没有那么好 在实验上和理论上， 类型 内变是很重要的，特别是因为它们的形成 比基于基因组内容的随机性估计更频繁， 预测。 高频源于邻近效应，这增强了 如果两个DSB是 最初形成时靠得很近，如果两个DSB都打开， 相同的染色体。 例如，倒位在致癌作用中起作用 类似于易位，它们可能几乎和 易位，因为有这么多的小倒位;同样，小 缺失可能是致癌的。 该赠款将承担理论和 计算机计算，将邻近效应与低或低变化的内部变化联系起来 高LET到大规模间期染色质几何学。 新聚合物 G 0/G1期大尺度染色质构象的模型将得到扩展 以结合染色质束缚和染色质运动。 聚合物模型 导致对变化内大小谱的预测;例如估计 在太小而不能在显微镜下观察到的内部变化的频率上 可以从观察到的组内与组间的比值中得出 内部变化。 提出了机械计算机和生物物理建模， 一种相对便宜的方法，以最大限度地提高信息可获得的 来自畸变数据库的快速增长的染色质几何形状，以及 来指导实验