Control of Cell Cycle Transitions

描述（由申请人提供）：真核细胞的分裂必须以高度忠实的方式发生。在细胞周期的过程中，细胞必须能够非常忠实地复制它们的DNA。此外，当复制过程中出现问题时，细胞必须在试图纠正病变时施加检查点介导的细胞周期停滞。最近，我们发现了一种新的蛋白质，称为Treslin，这是必不可少的DNA复制在脊椎动物细胞中Treslin行为在细胞复制的关键监管环节。特别是，Treslin是细胞周期蛋白依赖性激酶（CDK）的一个关键靶点，CDK促进复制起点的初始启动 在S期开始时。此外，Treslin似乎也参与了检查站管理。 对于本提案中的研究，我们将对Treslin及其与S期其他关键调节因子的功能关系进行深入分析。我们将在爪蟾卵提取物和人类细胞中进行这些研究。鸡蛋提取物系统提供了一些目前人类细胞所不具备的技术优势。许多研究表明，这种非洲爪蟾系统提供了一个有效的人类细胞模型。总的来说，我们将试图揭示Treslin如何促进脊椎动物基因组的准确复制和维持，以及细胞如何控制Treslin的活性。特别是，我们将分析Treslin的各种结构域，以阐明其功能架构。我们将研究Treslin与其他复制蛋白的合作如何有助于其功能。我们将研究 进一步了解磷酸化如何控制Treslin的功能特性。此外，我们还将研究Treslin在检查点响应中的作用。最后，我们将尝试识别Treslin的新伙伴，并阐明这种蛋白质的潜在新功能。 总的来说，这些研究有望对细胞如何在其整个生命周期中保持基因组完整性产生有价值的见解。这一信息对人类健康尤其重要。由于环境损害或遗传突变或两者的结果，基因组完整性的紊乱可导致各种人类病理，最显著的是癌症。因此，彻底了解基因组不稳定性的根本原因对于对抗癌症的明智策略至关重要。

DESCRIPTION (provided by applicant): The division of eukaryotic cells must occur in a highly faithful manner. During the course of the cell cycle, cells must be able to replicate their DNA with great fidelity. Furthermore, when problems arise during replication, cells must impose a checkpoint-mediated arrest of the cell cycle while they attempt to rectify lesions. Recently, we identified a novel protein called Treslin that is essential for DNA replication in vertebrate cells Treslin acts at a critical regulatory juncture in cellular duplication. In particular, Treslin is akey target of the cyclin-dependent kinase (CDK) that promotes the initial firing of replication origins at the onset of S-phase. Moreover, Treslin also appears to participate in checkpoint regulation. For the studies in this proposal, we will carry out an intensive analysis of Treslin and its functional relationships with other key regulators of S-phase. We will conduct these investigations in both Xenopus egg extracts and human cells. The egg-extract system offers some technical advantages that are not available currently with human cells. Numerous studies have indicated that this Xenopus system offers a valid model for human cells. Overall, we will attempt to reveal how Treslin promotes accurate replication and maintenance of the genome in vertebrates and how cells control the activity of Treslin. In particular, we will analyze the varios domains of Treslin in order to elucidate its functional architecture. We will examine how the collaboration of Treslin with other replication proteins contributes to its function. We will study further how phosphorylation controls the functional properties of Treslin. Moreover, we will also investigate the role of Treslin in checkpoint responses. Finally, we will attempt to identify new partners of Treslin and elucidate potentially novel functions of this protein. In general, these studies hold the promise to yield valuable insights into how cells maintain genomic integrity throughout their lifetimes. This information would be especially relevant for human health. Derangement of genomic integrity as a consequence of environmental insults or inherited mutations or both can result in various human pathologies, most notably cancer. Thus, a thorough understanding of the root causes for genomic instability will be essential for an informed strategy in combating cancer.