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: 7065584
• 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/7065584
• 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）：乳腺癌占每年美国女性诊断出的新癌症总数的惊人32％。这些病例中最多有10％是由肿瘤抑制基因BRCA1突变引起的。正常细胞中BRCA1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BRCA1一起功能，以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，而Bach 1是癌症基因本身的产物。 为了阐明Bach1的生物学特性，我们利用生物化学，哺乳动物细胞培养和鼠模型的结合。初步结果强烈表明Bach1参与对DNA损伤的反应。像BRCA1一样，Bach1在通过磷酸化的DNA损伤后修饰，这一事件对于其作为DNA机械师的活性至关重要。此外，与疾病相关的BACH1编码区域的序列改变会导致解旋酶有缺陷，从而在Bach1活性与疾病发展之间提供了生化联系。具体而言，该项目的目的是：1）定义Bach1在细胞增殖和DNA修复中的作用； 2）检查DNA后DNA损伤引起的Bach1磷酸化的性质和意义对Bach1生物学功能； 3）评估Bach1是否是癌基因的产物。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。首席研究员罗尼·德拉普金（Ronny Drapkin）博士是医学博士，他已经完成了解剖病理学的住院医师培训，并希望发展独立的研究职业，重点是癌症发展和进展中的致癌事件。赞助商戴维·利文斯顿（David Livingston）博士是一位公认的癌症生物学世界领导者，培训成功的基本研究人员的记录很强。