Defining the DNA damage pathway in faithful mitotic progression

定义忠实有丝分裂进展中的 DNA 损伤途径

• 批准号: 10177975
• 负责人: Lilian Carolina Kabeche
• 金额: $ 18.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-02 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177975
• 关键词: ATR gene; Affect; Aneuploidy; Award; Binding; Breast cancer metastasis; Cancer Biology; Cancer Model; Cancer cell line; Cell Cycle Arrest; Cell Line; Cells; Cellular biology; Centromere; Cessation of life; Chromosomal Instability; Chromosome Segregation; Chromosomes; Congenital Abnormality; DNA Damage; DNA Repair; DNA biosynthesis; Defect; Diploidy; Drug resistance; Ensure; Event; Exhibits; Genetic Materials; Genetic Variation; Genome Stability; Genomic Instability; Goals; Hematologic Neoplasms; Immune; Immune Evasion; Institution; Interphase; Karyotype; Lead; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mass Spectrum Analysis; Mediator of activation protein; Mitosis; Mitotic; Mus; Neoplasm Metastasis; Organism; Pathway interactions; Patients; Phenotype; Phosphotransferases; Population; Positioning Attribute; Process; Prognosis; Proteins; Publishing; Research; Research Personnel; Role; S Phase; Single-Stranded DNA; Site; Solid Neoplasm; Test Result; Testing; Therapeutic; Time; Tumorigenicity; cancer cell; cancer therapy; career; chemotherapy; chromosome missegregation; effective therapy; faculty research; inhibitor/antagonist; malignant breast neoplasm; mouse model; neoplastic cell; novel; prevent; recruit; replication stress; response; segregation; skills; success; targeted cancer therapy; therapy resistant; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Genomic instability is a hallmark of cancer and correlated with overall poor patient prognosis. A specific form of genomic instability is chromosomal instability (CIN), which occurs when a cell continuously missegregate their chromosomes leading to changes in karyotype. CIN is a common feature of cancer – with approximately 90% of solid tumors and 50% of hematopoietic cancers exhibiting CIN. CIN is also correlated with increased tumor progression and poor patient prognosis. However, the levels of CIN must be maintained at an optimal level, because too high levels of missegregation events are deleterious to cells. This creates a therapeutic window by which chemotherapies can exploit CIN to create effective treatments against cancer cells. ATR, a master regulator of DNA damage repair pathways, ensures genomic stability by promoting DNA damage repair and timely replication. I recently showed that ATR also promotes genomic stability by promoting faithful chromosome segregation in mitosis and preventing CIN. In this application, I propose to investigate the mechanism by which ATR is activated in mitosis (Aim 1), identify its substrate network (Aim 2) and use ATR inhibition to target CIN cancer cells specifically (Aim 3). My proposed studies may reveal more novel functions of ATR in mitosis and allow us to better understand of how mitotic processes are regulated by ATR and other DDR proteins to ensure proper chromosome segregation. This in turn, will give us a better understanding of the overlap of mitotic and DDR proteins in ensuring genomic stability. Lastly, I hope that developing a strategy to specifically kill CIN cancer cells will be a breakthrough in targeted cancer therapies. My career goal is to obtain a research faculty position at a leading institution where I will dissect the mechanisms by which ATR and other DDR proteins regulate chromosome segregation. My successful transition would be bolstered by augmenting my expertise in cell biology, mass spectrometry and mouse cancer models. I will use these acquired skills to investigate whether ATR inhibitors can be used to specifically target CIN cancer cells. Importantly, the protected time that this award provides me will allow me to elucidate the mechanism by which ATR is activated and determine if ATR inhibitors can be used to exploit CIN in cancer cells. Furthermore, the success of this project will be greatly enhanced by the outstanding collaborators that I will have advise me through the K22 period. The receipt of this award will allow me to expand my research plan and establish myself as a primary investigator in the field of cancer biology.

项目摘要/摘要 基因组不稳定性是癌症的标志，与总体差的患者提示相关。特定的 基因组不稳定性的形式是染色体不稳定性（CIN），当细胞继续错误地分析时发生 它们的染色体导致核型变化。 CIN是癌症的常见特征 - 大约 90％的实体瘤和50％的造血癌表现出CIN。 CIN也与增加 肿瘤进展和患者进展不佳。但是，CIN的水平必须保持在最佳状态 级别，因为过高的错误分析事件对细胞是有害的。这会创建一种疗法 化学疗法可以利用CIN创建有效治疗癌细胞的窗口。 atr，a DNA损伤修复途径的主要调节剂，通过促进DNA损伤修复来确保基因组稳定性 和及时复制。我最近表明，ATR还通过促进忠实而促进基因组稳定性 有丝分裂和防止CIN的染色体分离。在此应用程序中，我建议调查 在有丝分裂中激活ATR的机制（AIM 1），识别其底物网络（AIM 2）并使用ATR 特别针对CIN癌细胞的抑制作用（AIM 3）。我提出的研究可能揭示了更多新颖的功能 ATR有丝分裂的作用，使我们能够更好地了解有丝分裂过程如何受ATR和其他的调节 DDR蛋白以确保正确的染色体分离。反过来，这将使我们对 有丝分裂和DDR蛋白在确保基因组稳定性方面的重叠。最后，我希望制定一种策略 特异性杀死CIN癌细胞将是靶向癌症疗法的突破。 我的职业目标是在领先的机构中获得研究教师职位，我将剖析 ATR和其他DDR蛋白调节染色体分离的机制。我成功的过渡 通过增强我在细胞生物学，质谱和小鼠癌模型方面的专业知识来增强我的支持。 我将使用这些获得的技巧来研究ATR抑制剂是否可以专门针对CIN Cancer 细胞。重要的是，该奖项给我的受保护时间将使我能够通过 该ATR被激活并确定是否可以使用ATR抑制剂来利用癌细胞中的CIN。此外， 杰出的合作者将大大提高该项目的成功，我将为我提供建议 在K22期间。该奖项的收到将使我扩大我的研究计划并确定自己 作为癌症生物学领域的主要研究者。