A Novel Protein Complex Controls Homologous Recombination Repair in Breast Cancer

一种新型蛋白质复合物控制乳腺癌的同源重组修复

基本信息

批准号：
8700611
负责人：
Jingsong Yuan
金额：
$ 16.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700611
关键词：
Affinity Chromatography Antineoplastic Agents BRCA1 gene BRCA2 gene Binding Binding Proteins Bioinformatics Breast Cancer Cell Breast Cancer Patient Breast Cancer Prevention Breast Cancer Treatment Breast Cancer cell line Camptothecin Cancer Etiology Cancer Patient Cancer-Predisposing Gene Cell Cycle Cells Cisplatin Clinical Management Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Data Defect Development Diagnosis G2 Phase Genes Genomic Instability Goals Health Hereditary Breast Carcinoma Human Incidence Ionizing radiation Knockout Mice Knowledge Lead Malignant Neoplasms Molecular Mus Mutate Mutation Names Nonsense Mutation Pathway interactions Pharmaceutical Preparations Play Prevention strategy Process Proteins Rad51 recombinase Recruitment Activity Regimen Research Risk Factors Role S Phase Sampling Sister Chromatid Site Testing Therapeutic Tissue Sample Translations Tumor Suppressor Proteins cancer therapy chemotherapy clinical practice design drug sensitivity exome sequencing homologous recombination improved in vivo inhibitor/antagonist malignant breast neoplasm mortality novel protein complex recombinase recombinational repair repaired research study response therapy development tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Inheritance of mutations in one of the breast cancer susceptibility genes, BRCA1 or BRCA2, is the most significant risk factor for developing breast cancer. BRCA1 and BRCA2 are known to function in a common DNA repair pathway, named homologous recombination (HR). HR is an essential DNA repair process that uses the homologous sister chromatid to carry out accurate repair of DNA double-strand breaks (DSBs), predominantly taking place during S and G2 phases of the cell cycle. However, while BRCA1 and BRCA2 are frequently mutated in familial breast cancers, mutations of these tumor suppressors are rare in sporadic breast cancers, raising the possibility that other genes involved in HR repair pathway, but not BRCA1 or BRCA2, may be mutated or dysregulated in sporadic breast cancers. In fact, HR deficiencies are frequently present in sporadic breast cancers (defined as a BRCAness or BRCA-like profile). To better understand the function of HR defects in sporadic breast cancer development, we have to know more about HR pathway by identifying novel HR factors other than the known BRCA1 and BRCA2 tumor suppressors. The BRCA2-interacting protein, RAD51, is at the center of HR pathway. This proposed project focuses on identifying a set of new RAD51-associated HR factors, including FIGNL1, KIAA0146 and C1orf112, and testing their potential roles in breast cancer development and treatment. The specific aims are: Aim 1: Elucidate the molecular functions of FIGNL1 protein complex in HR repair; Aim 2: Evaluate the functions of FIGNL1 in tumorigenesis; Aim 3: Determine the potential roles of FIGNL1 protein complex in breast cancer development and therapy. The proposed study is expected to identify novel factors involved in HR repair and generate important knowledge for understanding breast cancer etiology, which may have great implications for the clinical management of breast cancer patients.

描述（由申请人提供）：乳腺癌易感基因之一（BRCA1 或 BRCA2）的突变遗传是发生乳腺癌的最重要的风险因素。已知 BRCA1 和 BRCA2 在共同的 DNA 修复途径中发挥作用，称为同源重组 (HR)。 HR 是一个重要的 DNA 修复过程，它使用同源姐妹染色单体对 DNA 双链断裂 (DSB) 进行精确修复，主要发生在细胞周期的 S 期和 G2 期。然而，虽然 BRCA1 和 BRCA2 在家族性乳腺癌中频繁突变，但这些肿瘤抑制基因的突变在散发性乳腺癌中很少见，这增加了参与 HR 修复途径的其他基因（但 BRCA1 或 BRCA2 除外）可能在乳腺癌中发生突变或失调的可能性。散发性乳腺癌。事实上，HR 缺陷经常出现在散发性乳腺癌（定义为 BRCA 或 BRCA 样特征）中。为了更好地了解 HR 缺陷在散发性乳腺癌发展中的功能，我们必须通过识别除已知的 BRCA1 和 BRCA2 肿瘤抑制因子之外的新 HR 因子来更多地了解 HR 通路。 BRCA2 相互作用蛋白 RAD51 位于 HR 通路的中心。该拟议项目的重点是确定一组新的 RAD51 相关 HR 因子，包括FigNL1、KIAA0146 和 C1orf112，并测试它们在乳腺癌发展和治疗中的潜在作用。具体目标是：目的1：阐明FIGNL1蛋白复合物在HR修复中的分子功能；目标2：评估FIGNL1在肿瘤发生中的功能；目标 3：确定FigNL1 蛋白复合物在乳腺癌发生和治疗中的潜在作用。拟议的研究有望确定参与 HR 修复的新因素，并为了解乳腺癌病因学提供重要知识，这可能对乳腺癌患者的临床管理产生重大影响。