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

• 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
• 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

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） 摘要： DNA损伤的忠实修复和停滞复制叉的有效解决是根本 哺乳动物细胞维持DNA序列保真度和染色体完整性的机制 复制和对外源DNA损伤的反应。DNA修复机制的缺陷不仅会导致 基因组不稳定性和随后的肿瘤发生，而且还可以改变细胞的表观遗传景观， 赋予了可以在临床上利用的治疗弱点。参与本P01项目的研究者 在理解细胞保持基因组完整性以抑制 肿瘤发生，并在暴露肿瘤的脆弱性，以治疗的基础上，机械的理解， 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 多学科方法来理解BRCA 1-PALB 2-BRCA 2 复杂的和相关的调节因子参与调节DNA复制和修复选择。监管机构 BRCA-网络包括53 BP 1、RNF 4、BARD 1、TOPBP 1、EHMT 2（G9 a）、MCM 10、SLFN 11（小鼠Slfn 9）和 BCCIP。其中一些因素一直是项目组调查人员长期以来的研究重点。 研究合作围绕着这个大型蛋白质网络的成员如何形成的中心主题 相互作用以维持基因组完整性、抑制肿瘤发展和调节肿瘤 对癌症治疗的反应。四个项目、两个共享资源核心和一个管理核心， 提出了实现三个科学目标：1）揭示新的机制，其中招聘和功能 BRCA 1-PALB 2-BRCA 2网络的表达受染色质环境的调节，染色质环境由甲基化，类小泛素化， 和泛素化; 2）完善BRCA网络在DNA复制，肿瘤抑制和定义中的作用。 BRCA功能障碍的基因组后果;和3）探索新的机会，靶向缺陷， BRCA神经管母细胞瘤和乳腺癌治疗网络。