BACH1 Function in DNA Repair and Mammary Oncogenesis

BACH1 在 DNA 修复和乳腺肿瘤发生中的功能

• 批准号: 6927383
• 负责人: Ronny I DRAPKIN
• 金额: $ 13.6万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927383
• 关键词: DNA damage; DNA repair; RNA interference; brca gene; breast neoplasms; cell proliferation; cytogenetics; enzyme activity; enzyme mechanism; helicase; histopathology; laboratory mouse; mammary epithelium; neoplasm /cancer genetics; neoplastic process; phosphorylation; protein localization; pulsed field gel electrophoresis; radiation sensitivity; small interfering RNA; tissue /cell culture

DESCRIPTION (provided by applicant): Breast cancer accounts for a staggering 32% of the total number of new cancer cases diagnosed in American women each year. Up to 10% of these cases are caused by mutations on the tumor suppressor gene BRCA1. The physiological and biochemical function of BRCA1 in normal cells remains elusive. The recently described BACH1 DNA helicase functions together with BRCA1 to mediate efficient repair of double strand breaks. The proposal hypothesizes that the DNA repair and tumor suppression functions of BRCA1 are intimately linked to BACH1 function and that BACH 1 is the product of a cancer gene itself. In order to elucidate the biological properties of BACH1, we are utilizing a combination of biochemistry, mammalian cell culture, and murine models. Preliminary results strongly suggest that BACH1 participates in the response to DNA damage. Like BRCA1, BACH1 is modified upon DNA damage by phosphorylation, an event that is critical for its activity as a DNA mechanic. Moreover, disease-associated sequence alterations in the BACH1 coding region result in defective helicase enzymes, providing a biochemical link between BACH1 activity and disease development. Specifically, the project aims to: 1) define the role of BACH1 in cellular proliferation and DNA repair; 2) examine the nature and significance of post-DNA damage induced BACH1 phosphorylation on BACH1 biological function; and 3) assess whether BACH1 is the product of a cancer gene. The long-term goals are to better understand the connection between genome integrity control and oncogenesis. Dr. Ronny Drapkin, the principal investigator, is an M.D., Ph.D., who has completed residency training in anatomic pathology, and wishes to develop an independent research career focusing on oncogenic events in cancer development and progression. The sponsor, Dr. David Livingston, is a recognized world-leader in cancer biology with a strong record of training successful basic investigators.

描述（由申请人提供）：乳腺癌占美国女性每年诊断出的新癌症病例总数的 32%，令人震惊。其中高达 10% 的病例是由抑癌基因 BRCA1 突变引起的。 BRCA1 在正常细胞中的生理和生化功能仍然难以捉摸。最近描述的 BACH1 DNA 解旋酶与 BRCA1 一起发挥作用，介导双链断裂的有效修复。该提案假设 BRCA1 的 DNA 修复和肿瘤抑制功能与 BACH1 功能密切相关，并且 BACH 1 是癌症基因本身的产物。 为了阐明 BACH1 的生物学特性，我们结合了生物化学、哺乳动物细胞培养和小鼠模型。初步结果强烈表明 BACH1 参与了对 DNA 损伤的反应。与 BRCA1 一样，BACH1 在 DNA 损伤时会通过磷酸化进行修饰，磷酸化对其作为 DNA 机制的活性至关重要。此外，BACH1 编码区中与疾病相关的序列改变会导致解旋酶缺陷，从而提供 BACH1 活性与疾病发展之间的生化联系。具体来说，该项目旨在：1）明确BACH1在细胞增殖和DNA修复中的作用； 2) 检查DNA损伤后诱导的BACH1磷酸化对BACH1生物学功能的性质和意义； 3) 评估BACH1是否是癌症基因的产物。长期目标是更好地了解基因组完整性控制与肿瘤发生之间的联系。主要研究者 Ronny Drapkin 博士是一名医学博士、哲学博士，已完成解剖病理学住院医师培训，并希望发展专注于癌症发生和进展中的致癌事件的独立研究生涯。资助者 David Livingston 博士是癌症生物学领域公认的世界领先者，在培训成功的基础研究人员方面拥有良好的记录。