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：
10408039
负责人：
Bing Xia
金额：
$ 38.19万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10408039
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 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 rational design 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.

项目摘要/摘要 PALB2是肿瘤抑制蛋白，在物理和功能上将BRCA1和BRCA2（两个主要）连接起来乳腺癌助推器，在DNA损伤反应和抑制肿瘤中。 3蛋白在A中起作用 BRCA1-PALB2-BRCA2轴可在同源重组（HR）的DNA双重双重作用中起重要作用 DNA损伤后，链断裂修复（DSBR）和细胞周期检查点控制。这些功能至关重要维持基因组稳定性和抑制肿瘤发生。近年来，很多了解了HR-DSBR中PALB2的机制，但是PALB2发挥作用的机制 BRCA2和BRCA1促进细胞周期检查点响应仍然难以捉摸，以及正常的PALB2突变体细胞在体内生存和增殖，并进化为癌细胞的进化知之甚少。在此提案中，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 AIM 1，我们将使用磷酸蛋白质组学，靶向蛋白质组学和功能研究来识别关键因素和 PALB2介导的G2/M检查点控制的机理。在AIM 2中，我们将基于我们最近发现的 PALB2突变小鼠中的NFκB激活，并结合系统性敲除，有条件的敲除，谱系跟踪和器官模型，以定义与PALB2相关乳腺肿瘤发生的机理 NFκB在此过程中的作用。在AIM 3中，我们将确定新的遗传机制通过测试palb2和brca1在乳腺肿瘤发育中发现了完全关系 RAD52和RNF168在各个模型中的作用。