Mechanisms of the BRCA-network in tumorigenesis and therapeutic response

BRCA 网络在肿瘤发生和治疗反应中的机制

基本信息

批准号：
10396606
负责人：
Zhiyuan Shen
金额：
$ 227.02万
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：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396606
关键词：
Ablation Address Area BARD1 gene BRCA1 gene BRCA2 gene Cells Chromatin Chromosomal Stability Chromosomes Clinical Collaborations Complex DNA Damage DNA Repair DNA Sequence DNA Sequence Alteration DNA biosynthesis DNA replication fork Data Defect Development Epigenetic Process Functional disorder Generations Genes Genetic Genetically Engineered Mouse Genomic Instability Genomics Goals Human Impairment In Vitro Kinetics Lead MCM10 gene Malignant Neoplasms Mammalian Cell Mammary Neoplasms Mediating Methods Methylation Modeling Molecular Mus Mutagenesis Mutation PALB2 gene Pathway interactions Pattern Pharmaceutical Preparations Program Research Project Grants Proteins Recurrence Regulation Research Research Personnel Resolution Resource Sharing Role Site Structure Suggestion Sumoylation Pathway TOP1 gene TOPBP1 Gene Therapeutic Tumor Suppression Ubiquitination base cancer therapy chemotherapy design gene network genome integrity genomic signature genomic tools homologous recombination improved improved outcome inhibitor insight interdisciplinary approach interest loss of function malignant breast neoplasm medulloblastoma member mouse model mutant novel novel therapeutics p53-binding protein 1 programs public health relevance recruit repaired replication stress response success targeted cancer therapy targeted treatment tool treatment response tumor tumorigenesis ubiquitin-protein ligase

项目摘要

Mechanisms of the BRCA-network in Tumorigenesis and Therapeutic Response (OVERALL) Abstract: The faithful repair of DNA damage and efficient resolution of stalled replication forks are fundamental mechanisms by which mammalian cells maintain DNA sequence fidelity and chromosomal integrity during DNA replication and in response to exogenous DNA damage. Defects in DNA repair mechanisms not only contribute to genomic instability and subsequent tumorigenesis, but also can alter the epigenetic landscape of cells and impart therapeutic vulnerabilities that can be exploited clinically. The investigators participating in this P01 project share common interests in understanding the mechanisms by which cells maintain genomic integrity to suppress tumorigenesis, and in exposing tumor vulnerability to therapy based on mechanistic understandings of the genomic consequences of impaired DNA repair. One particularly strong area of research offered by this team is a multi-disciplinary approach to understanding the basic mechanisms by which the BRCA1-PALB2-BRCA2 complex and associated regulators participate in regulating DNA replication and repair choice. Regulators of the BRCA-network include, 53BP1, RNF4, BARD1, TOPBP1, EHMT2 (G9a), MCM10, SLFN11 (mouse Slfn9), and BCCIP. Some of these factors have been a long-standing research focus for investigators in the project team. The research collaboration is formed around the central themes of how members of this large network of proteins interface with each other to maintain genome integrity, suppress tumor development and modulate tumor response to cancer therapy. Four projects, two Shared Resource Cores, and an Administrative Core are proposed to achieve three scientific goals: 1) to reveal novel mechanisms by which the recruitment and function of the BRCA1-PALB2-BRCA2 network is regulated by chromatin context mediated by methylation, sumoylation, and ubiquitination; 2) to refine the roles of the BRCA network in DNA replication, tumor suppression and define the genomic consequences of BRCA dysfunction; and 3) to explore new opportunities to target defects in the BRCA network for therapeutics in medulloblastoma and breast cancer.

BRCA网络在肿瘤发生和治疗反应中的机制（总体上）抽象的： DNA损伤的忠实维修和停滞复制叉的有效分辨率是基本的哺乳动物细胞在DNA期间保持DNA序列保真度和染色体完整性的机制复制并响应外源性DNA损伤。 DNA修复机制中的缺陷不仅有助于基因组不稳定性和随后的肿瘤发生，但也可以改变细胞的表观遗传景观和可以在临床上剥削的治疗脆弱性。调查人员参加了这个P01项目在理解细胞维持基因组完整性以抑制的机制方面具有共同利益肿瘤发生，并根据对机械理解的理解暴露肿瘤脆弱性 DNA修复受损的基因组后果。该团队提供的一个特别强大的研究领域是一种多学科的方法，用于理解BRCA1-PALB2-BRCA2的基本机制复杂和相关的调节器参与调节DNA复制和修复选择。监管机构 BRCA网络包括53BP1，RNF4，BARD1，TOPBP1，EHMT2（G9A），MCM10，SLFN11（鼠标SLFN9）和 BCCIP。这些因素中的一些因素一直是项目团队研究人员的长期研究重点。研究合作是围绕这种大型蛋白质网络的中心主题形成的彼此接口以维持基因组完整性，抑制肿瘤发展并调节肿瘤对癌症治疗的反应。四个项目，两个共享资源核心以及一个行政核心是提议实现三个科学目标：1）揭示招聘和功能的新型机制 BRCA1-PALB2-BRCA2网络的含量受甲基化，sumoylation，sumoylation，sumoylation，sumoylation，和泛素化； 2）完善BRCA网络在DNA复制，抑制肿瘤中的作用 BRCA功能障碍的基因组后果； 3）探索针对靶向缺陷的新机会髓母细胞瘤和乳腺癌治疗的BRCA网络。