BRCA1 and Transcriptional Control in DNA Damage Response

我们的主要目标是了解人类乳腺癌易感基因（BRCA 1）的失活如何导致乳腺肿瘤的发生。 BRCA 1通过双重参与DNA双链断裂修复和DNA损伤诱导基因的转录调控来确保全球基因组的稳定性。 该提案旨在了解BRCA 1的看护功能如何通过其在转录控制中的作用而得以实现。 BRCA 1及其相关辅阻遏物CtIP已被证明可抑制GADD 45基因的转录，该基因在G2/M细胞周期检查点控制中起作用。 最近，我们发现了ZBRK 1，一种新的蛋白质，结合到一个特定的DNA序列元件存在于一个子集的DNA损伤诱导BRCA 1靶基因和抑制转录通过其同源结合位点在BRCA 1依赖的方式。 基于这些初步的观察，我们假设ZBRK 1，BRCA 1，和CtIP协同抑制一组功能多样的DNA损伤反应基因在没有遗传毒性应激。 为了支持我们的假设，我们提出了以下目标，以定义和表征分子细节的生物学作用ZBRK 1作为一个直接的联系DNA损伤诱导的信号，BRCA 1和CtIP和转录控制其下游效应。 目标1. ZBRK 1和BRCA 1在功能多样的DNA损伤反应基因（包括GADD 45和MnSOD基因）的协同转录调控中的作用。 目的2是阐明电离辐射（IR）诱导的位点特异性磷酸化在体内ZBRK 1及其相关辅阻遏物BRCA 1和CtIP之间的功能相互作用网络中的作用。 目的3：通过对Ctip和Zbrk 1基因的种系失活研究，确定其在IR应答中的生物学作用。 这些研究可能会揭示BRCA 1，可能还有ZBRK 1和CtIP在保持基因组稳定性方面的看守特性的潜在基础，并为未来干预乳腺癌提供明确的分子靶点。

Our major goal is to understand how inactivation of the human breast cancer susceptibility gene (BRCA1) leads to breast tumorigenesis. BRCA1 ensures global genome stability through its dual participation in DNA double-strand break repair and transcriptional regulation of DNA damage-inducible genes. This proposal aims to understand how the caretaker function of BRCA1 is subserved by its role in transcription control. BRCA1 and its associated corepressor CtIP have been shown to repress transcription of the GADD45 gene that functions in G2/M cell cycle checkpoint control. Recently, we discovered ZBRK1, a novel protein, that binds to a specific DNA sequence element present in a subset of DNA damage-inducible BRCA1 target genes and represses transcription through its cognate binding site in a BRCA1- dependent manner. Based upon these preliminary observations, we hypothesize that ZBRK1, BRCA1, and CtIP coordinately repress a functionally diverse group of DNA damage-response genes in the absence of genotoxic stress. To provide support for our hypothesis, we propose the following Aims to define and characterize in molecular detail the biological role ZBRK1 as a direct link between DNA damage induced signals that converge on BRCA1 and CtIP and transcriptional control of their downstream effectors. Aim 1. is to establish the role of ZBRK1 and BRCA1 in the coordinate transcriptional regulation of functionally diverse DNA damage-response genes including GADD45 and MnSOD genes. Aim 2 is to elucidate the role of ionizing radiation (IR)-induced site-specific phosphorylation on the network of functional interactions between ZBRK1 and its associated co-repressors BRCA1 and CtIP in vivo. And Aim 3 is to establish the biological role of Ctip and Zbrk1 in response to IR in mice by germline inactivation of each corresponding gene. These studies will likely reveal novel insight into the underlying basis for the caretaker properties of BRCA1, and possibly ZBRK1 and CtIP, in preserving genomic stability and provide defined molecular targets for future intervention of breast cancer.