BRCA1 and its cofactor in chemotherapy-associated cardiotoxicity

BRCA1 及其辅助因子在化疗相关心脏毒性中的作用

• 批准号: 8814679
• 负责人: GREGORY J. AUNE
• 金额: $ 19.51万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814679
• 关键词: Adult; Animal Model; Animals; Apoptosis; Area; Attenuated; BRCA1 gene; Cancer Survivor; Cancer Survivorship; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cells; Complex; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA biosynthesis; DNA lesion; Development; Double Strand Break Repair; Doxorubicin; Doxorubicin-DNA Complex; Echocardiography; Energy Metabolism; Environment; Gene Expression; Generations; Genes; Genetic Transcription; Genotoxic Stress; Knock-out; Knowledge; Lead; Light; Link; Mammals; Mammary Gland Parenchyma; Mediating; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Mus; Myocardium; Pathway interactions; Play; Polymerase; Positioning Attribute; Production; Proliferating; Proteins; RNA Polymerase II; Recruitment Activity; Research; Role; Staging; Stress; Technology; Testing; Time; Tissues; Topoisomerase II; Toxic effect; Translations; Work; base; cancer cell; cancer diagnosis; chemotherapeutic agent; chemotherapy; childhood cancer survivor; cofactor; genotoxicity; homologous recombination; improved; insight; metabolomics; mortality; negative elongation factor; novel; overexpression; promoter; public health relevance; repaired; research study; response; tool; transcription factor

 DESCRIPTION (provided by applicant): With earlier-stage cancer diagnosis and improved efficacy of chemotherapy, doxorubicin-induced cardiotoxicity has increasingly become a significa nt cause of morbidity and mortality among cancer survivors. For example, the cardiac mortality of long-term pediatric cancer survivors is estimated to be more than eight times higher than expected. A major challenge in reducing therapy-associated cardiotoxicity is the paucity of knowledge about the molecular players and pathways that can mitigate the undesired effects of doxorubicin on myocardium. Doxorubicin targets topoisomerase II (Top2) by forming a ternary Top2-doxorubicin-DNA complex, which can lead to DNA breaks and ultimately trigger apoptosis. Mammals have two Top2-encoding genes, Top2αand Top2β. Top2α is overexpressed in dividing cancer cells and most likely serve as a primary target of the antitumor activity of doxorubicin. In contrast, Top2β is expressed in postmitotic cardiomyocytes and mediates the cardiotoxic effect of doxorubicin through its association with promoters of metabolism-related genes. As cardiomyocytes have a high demand for energy production, especially under stressed conditions, it raises the possibility that transcription factors important for energy metabolism-related gene expression may alleviate doxorubicin-induced, Top2β-mediated cardiotoxicity. Cofactor of BRCA1 (COBRA1) is a BRCA1-interacting protein discovered in the PI's lab. It is part of the negative elongation factor (NELF) that regulates transcription through RNA polymerase II (Pol II) pausing. Our preliminary work indicates that COBRA1 in cardiomyocytes plays an important role in sustaining transcription of energy metabolism-related genes. Importantly, cardiomyocyte-specific deletion of COBRA1 or BRCA1 exacerbates doxorubicin-induced cardiotoxicity. Given the physical interaction between BRCA1 and COBRA1, we hypothesize that these two proteins jointly mitigate doxorubicin-induced cardiotoxicity by (1) sustaining transcription of energy metabolism-related genes and (2) counteracting Top2β-mediated genotoxic stress preferentially at the promoters of these genes. Our application is conceptually novel because it explores a previously unappreciated connection between energy metabolism-related transcription and doxorubicin-induced cardiotoxicity. In addition, our proposed work challenges the prevailing DNA repair- centric paradigm for BRCA1 and seeks to elucidate an intriguing functional link between BRCA1/COBRA1 and Pol II pausing in a postmitotic tissue context. By integrating different cutting-edge technologies and aligning historically separate research areas, this trans-disciplinary research team strives to provide insights into a clinically important yet mechanistically under-explored problem in chemo-toxicity and long-term cancer survivorship.

 描述（由适用提供）：阿霉素诱导的心脏毒性具有更早的癌症诊断和提高的化学疗法效率，在癌症存活中造成了发病率和死亡率的重要原因。例如，估计长期儿科癌症生存的心脏死亡率估计是预期的八倍以上。减少治疗相关的心脏毒性的主要挑战是对分子玩家和途径的知识很少，这些知识可以减轻阿霉素对心肌的不受欢迎的影响。阿霉素靶向拓扑异构酶II（top2），形成三元顶2-二氧化糖素-DNA复合物，这可以导致DNA断裂并最终触发凋亡。哺乳动物具有两个TOP2编码基因，TOP2α和TOP2β。 TOP2α在分裂癌细胞中过表达，很可能是阿霉素抗肿瘤活性的主要靶标。相比之下，TOP2β在有丝分裂后心肌细胞中表达，并通过其与代谢相关基因的启动子的关联来介导阿霉素的心脏毒性作用。由于心肌细胞对能源产生的需求很高，尤其是在压力条件下，因此可以使与能量代谢相关的基因表达重要的转录因子可能减轻毒素毒素诱导的TOP2β介导的心脏毒性。 BRCA1（CoBra1）的辅因子是在PI实验室中发现的BRCA1相互作用蛋白。它是通过RNA聚合酶II（POL II）暂停转录的负伸长因子（NELF）的一部分。我们的初步工作表明，心肌细胞中的Cobra1在维持与能量代谢相关的基因的转录中起着重要作用。重要的是，Cobra1或BRCA1的心肌细胞特异性缺失加剧了阿霉素诱导的心脏毒性。鉴于BRCA1与CoBRA1之间的物理相互作用，我们假设这两种蛋白质通过（1）通过（1）维持能量代谢相关基因的转录以及（2）应对TOP2β-介导的遗传毒性应激在这些基因的启动者上优先降低了能量代谢相关的基因的转录。我们的应用在概念上是新颖的，因为它探讨了与能量代谢相关的转录与阿霉素诱导的心脏毒性之间未经批准的联系。此外，我们提出的工作挑战了BRCA1的主要以DNA维修为中心的范式，并试图阐明在蒙蒙病后组织环境中暂停BRCA1/COBRA1和POL II之间的有趣的功能联系。通过整合不同的尖端技术并使历史上分开的研究领域保持一致，该跨学科研究团队致力于在化学毒性和长期癌症生存方面提供有关临床上重要但机械探索的问题的见解。