The role of a BRCA1 associated complex in DNA damage response and tumor suppression

摘要 遗传性乳腺癌和卵巢癌肿瘤抑制蛋白BRCA 1在乳腺癌和卵巢癌中起着关键作用。 DNA修复、细胞周期检查点控制和基因组稳定性的维持。BRCA 1被招募到DNA中 通过BRCA 1相关复合物损伤位点，BRCA 1-A复合物响应电离 辐射Abraxas是BRCA 1-A复合物中的中心衔接蛋白，与BRCA 1 BRCT结合 结构域以磷酸化依赖的方式。我们已经证明，Abraxas发挥着重要的作用， 在抑制小鼠肿瘤发展中的作用，Abraxas和BRCA 1之间的相互作用是 对于Abraxas在修复DNA和维持基因组稳定性方面的功能至关重要，表明Abraxas 是乳腺肿瘤抑制中BRCA 1信号的一部分。聚焦Abraxas在电离中的作用 辐射诱导的双链断裂修复和阐明Abraxas的调节机制 功能将提供Abraxas作为一种新的肿瘤抑制基因的作用的见解，并将揭示 其肿瘤抑制功能的重要新机制。在这个应用程序中，我们将首先调查一个 调控Abraxas介导的BRCA 1在DNA双链断裂处积聚的新机制 Abraxas蛋白C末端对电离辐射的双重磷酸化。二是 检查Abraxas的肿瘤相关体细胞突变，并确定其调控机制。 Abraxas在抑制基因组不稳定性和肿瘤发展中的功能。第三，我们将确定 Abraxas在乳腺肿瘤抑制中的作用，通过产生和检查乳腺特异性Abraxas- 缺陷小鼠模型。总之，我们的研究将确定Abraxas作为肿瘤抑制基因的作用 及其肿瘤抑制功能的调控机制。它将提供新的见解的原因 和乳腺癌的机制，并可能导致发现新的治疗Abraxas缺陷的方法。 乳腺癌

ABSTRACT The hereditary breast and ovarian cancer tumor suppressor protein BRCA1 plays critical roles in DNA repair, cell cycle checkpoint control, and maintenance of genomic stability. BRCA1 is recruited to DNA damage sites through a BRCA1-associated complex, the BRCA1-A complex in response to ionizing radiation. Abraxas is the central adaptor protein in the BRCA1-A complex and binds to BRCA1 BRCT domains in a phosphorylation-dependent manner. We have demonstrated that Abraxas plays an important role in suppressing tumor development in mice and that the interaction between Abraxas and BRCA1 is critical for Abraxas' function in repair of DNA and maintenance of genome stability, indicating that Abraxas is part of BRCA1 signaling in breast tumor suppression. Focusing on the role of Abraxas in ionizing radiation-induced double strand break repair and elucidating the regulatory mechanism for Abraxas's function will provide insights into the role of Abraxas as a novel tumor suppressor gene and will uncover novel mechanisms important for its tumor suppressor function. In this application, we will first investigate a novel mechanism regulating Abraxas-mediated BRCA1 accumulation at DNA double strand breaks through double-phosphorylation of the C-terminus of Abraxas in response to ionizing radiation. Second, we will examine the tumor-related somatic mutations of Abraxas and determine the regulatory mechanisms for the function of Abraxas in suppressing genomic instability and tumor development. Third, we will determine the role of Abraxas in breast tumor suppression by generating and examining mammary-specific Abraxas- deficient mouse models. Together, our study will determine the role of Abraxas as a tumor suppressor gene and the regulatory mechanisms for its tumor suppressor function. It will provide new insights into the causes and mechanisms of breast cancer and may lead to the discovery of new therapies for Abraxas-deficient breast cancer.