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: 10415991
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415991
• 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; Phenotype; Phosphotransferases; Population; Positioning Attribute; Process; 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; malignant breast neoplasm; mouse model; neoplastic cell; novel; patient prognosis; 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.

项目概要/摘要 基因组不稳定性是癌症的一个标志，与患者整体不良预后相关。具体的 基因组不稳定的一种形式是染色体不稳定（CIN），当细胞连续错误分离时就会发生这种情况 他们的染色体导致核型的变化。 CIN 是癌症的一个常见特征——大约 90% 的实体瘤和 50% 的造血系统癌症表现出 CIN。 CIN 还与增加 肿瘤进展和患者预后不良。然而，CIN 水平必须维持在最佳水平 水平，因为过高水平的错误分离事件对细胞有害。这创造了一种治疗 化疗可以利用 CIN 来创造针对癌细胞的有效治疗方法。 ATR，一个 DNA 损伤修复途径的主要调节因子，通过促进 DNA 损伤修复确保基因组稳定性 并及时复制。我最近表明，ATR 还可以通过促进忠实性来促进基因组稳定性 有丝分裂中的染色体分离和预防 CIN。在本申请中，我建议调查 有丝分裂中 ATR 被激活的机制（目标 1），识别其底物网络（目标 2）并使用 ATR 特异性抑制 CIN 癌细胞（目标 3）。我提出的研究可能会揭示更多新颖的功能 ATR 在有丝分裂中的作用，使我们能够更好地了解 ATR 和其他物质如何调节有丝分裂过程 DDR 蛋白确保染色体正确分离。反过来，这将使我们更好地了解 有丝分裂和 DDR 蛋白的重叠确保基因组稳定性。最后，我希望制定一项战略 特异性杀死CIN癌细胞将是癌症靶向治疗的突破。 我的职业目标是在领先机构获得研究教职，在那里我将剖析 ATR 和其他 DDR 蛋白调节染色体分离的机制。我的成功转型 我将通过增强我在细胞生物学、质谱和小鼠癌症模型方面的专业知识来增强我的能力。 我将利用这些获得的技能来研究 ATR 抑制剂是否可以用于特异性靶向 CIN 癌症 细胞。重要的是，该奖项为我提供的受保护时间将使我能够通过以下方式阐明该机制： 哪种 ATR 被激活，并确定 ATR 抑制剂是否可用于利用癌细胞中的 CIN。此外， 我将向我提供建议的杰出合作者将极大地促进该项目的成功 通过K22时期。获得这个奖项将使我能够扩大我的研究计划并确立自己的地位 作为癌症生物学领域的主要研究者。

项目成果

ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei.

• DOI: 10.1016/j.molcel.2023.09.003
• 发表时间: 2023-09
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Yoon Ki Joo;Elizabeth M. Black;Isabelle Trier;W. Haakma;Lee Zou;Lilian Kabeche