Molecular mechanisms of bacterial DNA replication

细菌DNA复制的分子机制

• 批准号: 444524292
• 负责人: Dr. Frederic Dominique Schramm
• 金额: --
• 依托单位: Centre for Bacterial Cell Biology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/444524292?language=en
• 关键词: Molecular; mechanisms; bacterial; DNA; replication

The faithful duplication of genetic material is imperative for the proliferation of all life. Initiating this process requires that the DNA double helix is locally unwound at specific sites termed “origins” to assemble a replicative machinery on each of the parental strands to synthesize the new DNA. Despite the fundamental importance of DNA replication, we still do not have a comprehensive picture of this process, especially not in the most abundant lifeform on earth, bacteria. Specifically, the initiation of bacterial DNA replication is not comprehensively understood. This is in particular due to the fact that we still do not know the function of many essential sequence elements in the bacterial replication origin. Important progress in elucidating bacterial origin functions was recently made by studying the origin of replication of Bacillus subtilis. This genetically tractable organism harbors an origin typical for bacteria and has proven to be an excellent model for the study of bacterial DNA replication. It was in this model organism that the “DnaA-trios” were discovered. These new essential sequence elements are widely conserved amongst bacteria and act as a basal system for origin unwinding. Critically however, the structure and function of essential origin sequences that reside distal to the DnaA-trios remain unknown.The proposed research project will elucidate the structure and function of these regions of the Bacillus subtilis origin of replication. To this end, I will systematically mutate origin sequence elements and the interacting replication initiator protein DnaA and characterize the consequences on DNA replication initiation in vivo and in vitro. The proposed study will significantly advance our knowledge about the general setup and function of bacterial replication origins and represents an essential foundation for a mechanistic understanding of bacterial DNA replication. Uncovering the mechanistic basis of DNA replication initiation in bacteria is essential for a better control of bacterial growth in industrial applications and when fighting infectious diseases. No currently known antibiotic directly targets DNA replication proteins; the development of compounds interfering with the activity or the assembly of the DNA replication machinery would yield a new group of antibiotics.

遗传物质的忠实复制对于所有生命的增殖至关重要。启动这一过程需要DNA双螺旋在被称为“起源”的特定位点局部解开，以便在每条亲本链上组装复制机器以合成新的DNA。尽管 DNA 复制具有根本重要性，但我们仍然没有全面了解这一过程，尤其是在地球上最丰富的生命形式细菌中。具体来说，细菌 DNA 复制的启动尚未得到全面了解。这尤其是因为我们仍然不知道细菌复制起点中许多必需序列元件的功能。最近通过研究枯草芽孢杆菌的复制起源，在阐明细菌起源功能方面取得了重要进展。这种基因上易于处理的生物体具有细菌的典型起源，并已被证明是研究细菌 DNA 复制的绝佳模型。正是在这种模式生物中，“DnaA-三重奏”被发现。这些新的必需序列元件在细菌中广泛保守，并充当起源解旋的基础系统。然而，重要的是，位于 DnaA-trios 远端的必需起源序列的结构和功能仍然未知。拟议的研究项目将阐明枯草芽孢杆菌复制起点的这些区域的结构和功能。为此，我将系统地突变起始序列元件和相互作用的复制起始蛋白 DnaA，并表征体内和体外对 DNA 复制起始的影响。这项研究将显着增进我们对细菌复制起点的一般设置和功能的了解，并为理解细菌 DNA 复制的机制奠定了重要基础。揭示细菌中 DNA 复制起始的机制基础对于在工业应用和对抗传染病时更好地控制细菌生长至关重要。目前已知的抗生素还没有直接针对 DNA 复制蛋白；干扰 DNA 复制机制的活性或组装的化合物的开发将产生一组新的抗生素。