Biomechanical Genome Dynamics: A Single-Molecule Look at How the Forces Acting on DNA Affect Cellular Function

生物力学基因组动力学：单分子研究作用于 DNA 的力如何影响细胞功能

• 批准号: 418251-2013
• 负责人: Milstein, Joshua
• 金额: $ 1.68万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=573558
• 关键词: Biomechanical; Genome; Dynamics; Single; Molecule

The interior of a cell is an extremely crowded world that is bustling with activity. Molecules such as DNA, RNA, proteins, polysaccharides, etc., repeatedly interact and collide with one another. DNA, for instance, is constantly being twisted, bent and displaced by these random collisions, so much so, that the cell has evolved to rely upon the noisy or 'stochastic' dynamical motion of DNA for a variety of functions. For instance, twist and tension along the DNA molecule can affect the expression of distant genes while loops that intermittently form along the molecule can actually switch genes on and off. The cell has also evolved mechanisms to counteract the effects of random collisions to the DNA. For instance, in bacteria, some segments of DNA are physically transported by the growth of tiny filaments that push pairs of DNA through the intracellular soup to opposite ends of the cell before the cell divides. We seek to develop a fundamental understanding of how the mechanics of DNA, which govern its dynamical behavior, affects the also somewhat noisy or stochastic process of gene expression and to uncover how the forces and dynamics at play within cells allow the cell to accurately distribute its DNA from one generation to the next. We will use biophysical techniques that allow us to observe and interact with individual DNA molecules, which is the most quantitative and direct way to study the mechanics and dynamics of DNA. These genome dynamics are vital to the operation and division of cells. Results within the bacterial systems we study will lead to insight into the more complicated world of plant and animal cells where functional errors in genome regulation and replication can have grave implications for agriculture and the bioeconomy of Canada. This research will also provide an exemplary, interdisciplinary training experience for both students and postdocs and lead to collaborative work across both Canada and internationally.

牢房的内部是一个极为拥挤的世界，充满了活动。 分子（例如DNA，RNA，蛋白质，多糖等）彼此反复相互作用并碰撞。 例如，DNA经常被这些随机碰撞的扭曲，弯曲和移动，以至于细胞已经演变为依赖DNA的嘈杂或“随机”动力学运动来实现多种功能。 例如，沿DNA分子的扭曲和张力会影响远处基因的表达，而沿分子间歇性形成的环实际上可以开关和关闭基因。 该细胞还发展了应对随机碰撞对DNA的影响的机制。 例如，在细菌中，一些小细丝的生长在细菌的生长上进行了物理运输，这些细丝将成对的DNA通过细胞内汤推向细胞分裂之前的细胞的相对端。我们试图对控制其动力学行为的DNA力学的基本了解也影响了基因表达的嘈杂或随机过程，并如何揭示细胞内的力和动态如何使细胞中的力和动力学如何将其DNA从一代中分配到下一代。 我们将使用生物物理技术，使我们能够观察并与单个DNA分子相互作用，这是研究DNA的力学和动力学的最定量，最直接的方法。 这些基因组动力学对于细胞的运行和分裂至关重要。我们研究的细菌系统中的结果将导致对植物和动物细胞的更复杂世界的见解，在这些植物和动物细胞中，基因组调节和复制中的功能错误可能对农业和加拿大的生物经济具有严重的影响。 这项研究还将为学生和博士后提供典范，跨学科的培训经验，并在加拿大和国际上进行协作工作。