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.

细胞内部是一个极其拥挤的世界，充满了活力。 分子如DNA、RNA、蛋白质、多糖等，相互影响，相互碰撞。 例如，DNA不断地被这些随机碰撞扭曲、弯曲和移位，以至于细胞已经进化到依赖于DNA的嘈杂或“随机”动力学运动来实现各种功能。 例如，DNA分子的沿着扭曲和张力可以影响远距离基因的表达，而沿沿着分子间歇形成的环实际上可以打开和关闭基因。 细胞还进化出了抵消随机碰撞对DNA影响的机制。 例如，在细菌中，一些DNA片段通过微小细丝的生长进行物理运输，这些细丝在细胞分裂之前将成对的DNA通过细胞内汤推到细胞的两端。我们试图发展一个基本的理解DNA的力学，它管理其动力学行为，影响基因表达的也有点嘈杂或随机的过程，并揭示如何在细胞内发挥的力量和动力学允许细胞准确地分配其DNA从一代到下一代。 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力学和动力学的最定量和最直接的方法。 这些基因组动态对细胞的运作和分裂至关重要。我们研究的细菌系统内的结果将导致深入了解植物和动物细胞的更复杂的世界，其中基因组调控和复制的功能错误可能对加拿大的农业和生物经济产生严重影响。 这项研究还将为学生和博士后提供示范性的跨学科培训经验，并导致加拿大和国际上的合作。