DNA Damaging Signaling in Human Cancer Cells

描述（由申请人提供）：许多广泛使用的抗癌药物具有基因毒性并激活细胞DNA损伤途径。这些信号转导通路的缺陷是结直肠癌、乳腺癌和其他常见癌症的常见特征，也可能在癌症易感个体中遗传。因此，对DNA损伤信号、致癌作用和癌症治疗之间关系的研究应该为这些领域提供重要的见解。该项目的目的是开发一个模型系统，用于人类癌细胞DNA损伤反应的三个关键调节因子的遗传评估。

DESCRIPTION (provided by applicant): Many widely used anticancer agents are genotoxic and activate cellular DNA damage pathways. Defects in these signal transduction pathways are frequent features of colorectal, breast, and other common carcinomas, and can also be inherited in cancer-prone individuals. Studies of the relationship between DNA damage signaling, carcinogenesis, and cancer therapy should therefore provide important insights into each of these areas. The aims of this project are to develop a model system for the genetic assessment of three key regulators of the DNA damage response in human cancer cells. Aim 1. Analysis of human CHK2 kinase in DNA damage responses. Recently a great deal has been learned about CHK2 and its roles in cell cycle regulation and cancer predisposition. The precise details of how this kinase normally regulates the cell cycle, and how it functions as a tumor suppressor remain controversial. This aim is to understand how CHK2 can direct the arrest of damaged cancer cells during discrete phases of the cell cycle, and how loss of CHK2 function might lead to genetic instability. Aim 2. Analysis of human CHK1 activation in DNA damage responses. CHK1 encodes a canonical cell cycle checkpoint regulator and therefore an important target of DNA damage based therapy. This Aim is intended to study the effects of CHK1 activation, the role of CHK1 in unchallenged cancer cells and the overlapping functions of CHK1 and the CHK2 tumor suppressor. Aim 3. Analysis of NBS1 mutation in DNA damage signaling. Mutated in cancer prone individuals with the Nijmegen Breakage Syndrome, the NBS1 gene represents an important link between human cancer and the transduction of DNA damage signals. This Aim is to model the pathogenic NBS1 mutations in a human cancer cell line. Such a model system will provide a unique opportunity to study NBS1 function in cell cycle arrest, repair of chromosome breaks and therapeutic sensitivity. The combination of the above studies should provide considerable insight into functions of DNA damage signal transduction pathways and their dysfunction in human cancers.