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Role of PALB2 in the DNA Damage Response and Cancer Suppression

PALB2 在 DNA 损伤反应和癌症抑制中的作用

基本信息

批准号：
10166774
负责人：
Bing Xia
金额：
$ 42.47万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10166774
关键词：
BRCA1 gene BRCA2 gene BRCA3 gene Behavior Binding Breast Breast Cancer Risk Factor Breast Epithelial Cells Cell Cycle Cell Cycle Checkpoint Cell division Cells Chromatin Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats DNA Damage DNA Double Strand Break DNA Repair Defect Development Double Strand Break Repair Event Fanconi&apos s Anemia Female Breast Carcinoma Genes Genetic Genetic Counseling Genome Stability Genomic Instability Germ-Line Mutation Hereditary Breast Carcinoma Human In Vitro Inherited Knock-in Knock-out Link Maintenance Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Modeling Molecular Morphogenesis Mus Mutant Strains Mice Mutate Mutation Oncogenes Oncogenic Organoids Ovarian PALB2 gene PLK1 gene Pancreas Pathway interactions Phosphorylation Play Population Study Prevention approach Process Prognosis Proliferating Prostate Proteins Proteomics Public Health RAD52 gene Residual state Role Testing Time Tumor Suppression Tumor Suppressor Proteins base cancer cell cancer risk cancer therapy clinical phenotype conditional knockout design follow-up homologous recombination in vivo innovation insight lifetime risk malignant breast neoplasm malignant stomach neoplasm mutant neoplastic cell novel strategies phosphoproteomics precision genetics precision medicine prevent protein function recruit repaired response tumor tumorigenesis

项目摘要

Project Summary/Abstract PALB2 is tumor suppressor protein that physically and functionally links BRCA1 and BRCA2, the two major breast cancer suppressors, in the DNA damage response and tumor suppression. The 3 proteins function in a BRCA1-PALB2-BRCA2 axis to play essential roles in in homologous recombination (HR)-based DNA double strand break repair (DSBR) and cell cycle checkpoint control after DNA damage. These functions are critical for the maintenance of genome stability and suppressing tumorigenesis. In recent years, much has been learned about the mechanisms of PALB2 in HR-DSBR, but the mechanisms by which PALB2 functions with BRCA2 and BRCA1 to promote cell cycle checkpoint response remain elusive, and how normal PALB2 mutant cells survive and proliferate in vivo and evolve into cancer cells is poorly understood. In this proposal, we will deploy a combination of state-of-the-art in vitro and in vivo approaches to answer the above open questions. In Aim 1, we will use phosphoproteomics, targeted proteomics and functional studies to identify key factors and mechanisms of PALB2-mediated G2/M checkpoint control. In Aim 2, we will build upon our recent discovery of NFκB activation in Palb2 mutant mice and use a combination of systemic knockin, conditional knockout, lineage tracing and organoid models to define the mechanisms of PALB2-associated mammary tumorigenesis and the role of NFκB in the process. In Aim 3, we will determine the genetic mechanisms of our newly discovered complementary relationship of PALB2 and BRCA1 in mammary tumor development by testing the roles of RAD52 and RNF168 in the respective models.

项目概要/摘要 PALB2 是肿瘤抑制蛋白，在物理和功能上连接 BRCA1 和 BRCA2（两个主要的癌症）乳腺癌抑制剂，参与 DNA 损伤反应和肿瘤抑制。这 3 种蛋白质的功能是 BRCA1-PALB2-BRCA2 轴在基于同源重组 (HR) 的 DNA 双链中发挥重要作用 DNA 损伤后的链断裂修复 (DSBR) 和细胞周期检查点控制。这些功能很关键用于维持基因组稳定性和抑制肿瘤发生。近年来，已经有很多了解了 PALB2 在 HR-DSBR 中的作用机制，但 PALB2 的作用机制与 BRCA2和BRCA1如何促进细胞周期检查点反应仍然难以捉摸，PALB2突变体如何正常人们对细胞在体内存活、增殖并进化成癌细胞的了解还知之甚少。在本提案中，我们将部署最先进的体外和体内方法的组合来回答上述开放问题。在目标1，我们将利用磷酸化蛋白质组学、靶向蛋白质组学和功能研究来确定关键因素和 PALB2 介导的 G2/M 检查点控制机制。在目标 2 中，我们将基于我们最近的发现 Palb2 突变小鼠中的 NFκB 激活并使用全身敲入、条件敲除、谱系追踪和类器官模型来定义 PALB2 相关乳腺肿瘤发生的机制以及NFκB在此过程中的作用。在目标 3 中，我们将确定新的遗传机制通过测试发现 PALB2 和 BRCA1 在乳腺肿瘤发展中的互补关系 RAD52 和 RNF168 在各自模型中的作用。