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：
8969966
负责人：
Bing Xia
金额：
$ 35.73万
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 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969966
关键词：
Accounting Apoptosis BRCA1 gene BRCA2 Mutation BRCA2 gene BRCA3 gene Binding Biochemical Biological Assay Cell Cycle Checkpoint Cells Chromatin Complex DNA DNA Damage DNA Double Strand Break DNA Repair Development Double Strand Break Repair Elements Embryo Etiology Family Fanconi&apos s Anemia Foundations Genes Genetic Genome Stability Germ-Line Mutation Hereditary Breast Carcinoma Inherited Investigation Kinetics Knockout Mice Link Maintenance Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Mammary gland Mediating Methylation Molecular Mouse Strains Mus Mutation Ovarian Pancreas Pathway interactions Phase Phosphorylation Play Prevention Property Proteins Publishing Radiation Reagent Recruitment Activity Reporter Resected Risk Role Signal Transduction Single-Stranded DNA Site Solid Somatic Mutation Specificity Testing Tissues Tumor Suppression Tumor Suppressor Proteins Tumor Tissue base cancer prevention cancer therapy cancer type clinical phenotype design homologous recombination in vivo insight malignant breast neoplasm mouse model mutant mutation carrier neoplastic cell novel novel strategies pre-clinical promoter protein function protein protein interaction public health relevance repaired replication factor A response tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): PALB2 is tumor suppressor protein that physically and functionally links BRCA1 and BRCA2, the two major breast cancer suppressors. The 3 proteins form a "BRCA" complex and function together in DNA double strand break (DSB) repair and cell cycle checkpoint control following DNA damage. These functions are critical for the maintenance of genome stability and suppressing tumorigenesis. We and others have shown that BRCA1 functions upstream of PALB2 and BRCA2. However, how BRCA1 regulates PALB2 in various DSB repair pathways remain poorly understood, and the mechanism how the 3 proteins promote checkpoint response remains unknown. Moreover, how much of BRCA1's tumor suppressive function is transmitted by PALB2 and to what extent PALB2's in vivo function depends on BRCA1 are also unknown. In this project, we will delve into the molecular underpinnings of the BRCA1- PALB2-BRCA2 DNA damage response network to understand key regulatory mechanisms that govern DSB repair efficiency, pathway choice and checkpoint control. Moreover, we will also use our newly generated Palb2 knockin mouse, in which the endogenous PALB2 is unable to bind BRCA1, to explore the etiology and tissue specificity of PALB2- and BRCA1-associated cancers. In Aim1, we will investigate the role and mechanism of the BRCA1-PALB2 interaction in homologous recombination (HR) and single strand annealing (SSA). In Aim2, we will define the mechanism of BRCA1, PALB2 and BRCA2 in the G2/M checkpoint control. In Aim3, we will use the above mouse model to explore the role of the BRCA1-PALB2 complex formation in the DNA damage response in vivo and in tumor suppression in different tissues.

描述（适用提供）：PALB2是肿瘤抑制蛋白，在物理和功能上将BRCA1和BRCA2（两个主要的乳腺癌补充剂）联系起来。 3蛋白在DNA双链断裂（DSB）修复和细胞周期检查点控制DNA损伤后形成“ BRCA”复合物，并在DNA双链断裂（DSB）中共同功能。这些功能对于维持基因组稳定性和抑制肿瘤发生至关重要。我们和其他人表明，BRCA1在PALB2和BRCA2上游功能。但是，在各种DSB修复途径中调节PALB2的BRCA1如何保持较低的理解，而3种蛋白如何促进检查点响应的机制仍然未知。此外，PALB2传递了BRCA1的抑制功能的多少，而PALB2的体内功能在多大程度上取决于BRCA1。在这个项目中，我们将深入研究BRCA1-PALB2-BRCA2 DNA损伤响应网络的分子基础，以了解控制DSB修复效率，途径选择和检查点控制的关键调节机制。此外，我们还将使用新生成的PALB2敲击小鼠，其中内源性PALB2无法结合BRCA1，以探索PALB2-和BRCA1相关癌症的病因和组织特异性。在AIM1中，我们将研究BRCA1-PALB2相互作用在同源重组（HR）和单链退火（SSA）中的作用和机制。在AIM2中，我们将在G2/M检查点控件中定义BRCA1，PALB2和BRCA2的机制。在AIM3中，我们将使用上述小鼠模型探索BRCA1-PALB2复合物形成在体内DNA损伤反应和不同组织中肿瘤抑制中的作用。