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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：
10599895
负责人：
Zhiyuan Shen
金额：
$ 226.92万
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：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599895
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 MCM10 gene Malignant Neoplasms Mammalian Cell Mammary Neoplasms Mediating Methods Methylation Modeling Molecular Mus Mutagenesis Mutation PALB2 gene Pathway interactions Pattern Pharmaceutical Preparations Poly(ADP-ribose) Polymerase Inhibitor Program Research Project Grants Proteins Recurrence Regulation Research Research Personnel Resolution Resource Sharing Role Site Structure 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 predictive tools 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作用机制(总体) 摘要：对DNA损伤的忠实修复和对停滞不前的复制叉的有效解决是根本哺乳动物细胞在DNA过程中维持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导致与基因组的不稳定性和随后的肿瘤发生有关，但也可以改变细胞和传授可在临床上利用的治疗脆弱性。参与P01项目的调查人员在理解细胞维持基因组完整性的机制方面有共同的兴趣肿瘤的发生，以及基于对肿瘤易感性的机械理解而进行的治疗 DNA修复受损的基因组后果。这个团队提供的一个特别强大的研究领域是多学科方法理解BRCA1-PALB2-BRCA2的基本机制复杂的和相关的调节因子参与调节DNA复制和修复选择。监管者： BRCA-网络包括53BP1、RNF4、BARD1、TOPBP1、EHMT2(G9a)、MCM10、SLFN11(鼠标SLFn9)和国商银行。其中一些因素一直是项目组研究人员的研究重点。这项研究合作是围绕着这个庞大的蛋白质网络的成员如何相互连接以维持基因组的完整性，抑制肿瘤的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是建议实现三个科学目标：1)揭示招聘和运作的新机制 BRCA1-PALB2-BRCA2网络的活性受染色质上下文调控，和泛素化；2)完善BRCA网络在DNA复制、肿瘤抑制和确定 BRCA功能障碍的基因组后果；以及3)探索新的机会来靶向髓母细胞瘤和乳腺癌治疗的BRCA网络。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

KMT2C-deficient tumors have elevated APOBEC mutagenesis and genomic instability in multiple cancers.

DOI：
10.1093/narcan/zcac023
发表时间：
2022-09
期刊：
NAR cancer
影响因子：
5.1
作者：
通讯作者：

Unmasking the mammalian SET domain-containing protein 4.

DOI：
10.1093/narcan/zcac021
发表时间：
2022-09
期刊：
NAR cancer
影响因子：
5.1
作者：
通讯作者：

Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma.

DOI：
10.1038/s42003-023-05668-3
发表时间：
2023-12-21
期刊：
COMMUNICATIONS BIOLOGY
影响因子：
5.9
作者：
Biswas, Antara;Sahoo, Sarthak;Riedlinger, Gregory M.;Ghodoussipour, Saum;Jolly, Mohit K.;De, Subhajyoti
通讯作者：
De, Subhajyoti

Redistribution of mutation risk in cancer.

癌症突变风险的重新分配。