A ROLE OF RAD51B IN DNA REPAIR AND BREAST CARCINOGENESIS

RAD51B 在 DNA 修复和乳腺癌发生中的作用

• 批准号: 6377090
• 负责人: Joanna S Albala
• 金额: $ 29.37万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377090
• 关键词: DNA damage; DNA repair; brca gene; breast neoplasms; carcinogenesis; cell line; cis platinum compound; gene expression; gene interaction; ionizing radiation; neoplasm /cancer genetics; p53 gene /protein; protein protein interaction; tissue /cell culture; tumor suppressor proteins; yeast two hybrid system

The long-term objective of this proposal is to elucidate the relationship of a newly identified human gene, RAD51B, to breast cancer-related genes and therefore, breast cancer. Sequence homology suggests that RAD51B is functionally similar to HsRAD51 (human RAD51). The HsRAD51 gene product has recently been shown to interact with the p53, BRCA1, and BRCA2 proteins. Mutations disrupting the BRCA1 and BRCA2 tumor suppressor genes result in familial breast and ovarian cancer. In addition, p53 mutations have been found in familial breast cancer as well as in a large proportion of other cancers. These studies suggest a role for the HsRASD51 gene in breast tumorigenesis. Furthermore, recent discoveries indicate that RAD51B associates with HsRAD51 within a multi-protein complex by its interaction with another HsRAD51 homolog, RAD51C. In general, the RAD51 family of proteins function in pathways essential for genome stability, and given the HsRAD51-BRCA interactions, the study of the RAD51B gene and its function may be critical for the understanding of breast cancer etiology. The proposed project will explore the relationship of RAD51B to identified complex partners by further characterizing the RAD51B-RAD51C interaction. Additional studies will identify novel binding partners of RAD51B by testing for specific interactions of RAD51B with both BRCA1 and BRCA2. Several recent studies have attempted to characterize the interactions of breast cancer-related gene products using immunocytochemical techniques. HsRAD51 and BRCA1 have shown to co-localize in nuclear foci in a malignant breast cell line. The proposed project will further the understanding of the role of RAD51B in pathways involved in genome stability and recombination by examining RAD51B in these cellular structures both before and after insult by DNA damage. The relationship of RAD51B to identified protein partners will be examined by the localization of these proteins in normal and malignant breast cell lines and meiotic synaptonemal complexes. Recent studies have shown that RAD51B is damage inducible and cells deficient in RAD51B in normal and malignant breast cancer cell lines treated with these agents will be explored. These studies will help to identify protein factors interacting with RAD51B and thus provide insights into the biological role of the protein and its putative link to breast cancer.

该提案的长期目标是阐明两者之间的关系 新发现的人类基因 RAD51B 与乳腺癌相关基因的关系 因此，乳腺癌。序列同源性表明 RAD51B 是 功能与 HsRAD51（人类 RAD51）相似。 HsRAD51基因产物具有 最近被证明与 p53、BRCA1 和 BRCA2 蛋白相互作用。 破坏 BRCA1 和 BRCA2 肿瘤抑制基因的突变会导致 家族性乳腺癌和卵巢癌。此外，还发现p53突变 在家族性乳腺癌以及大部分其他癌症中。 这些研究表明 HsRASD51 基因在乳腺肿瘤发生中的作用。 此外，最近的发现表明 RAD51B 与 HsRAD51 相关 通过与另一个 HsRAD51 同源物相互作用，在多蛋白复合物中， RAD51C。一般来说，RAD51 蛋白家族在重要途径中发挥作用 对于基因组稳定性，并考虑到 HsRAD51-BRCA 相互作用，该研究 RAD51B基因及其功能可能对于了解乳腺至关重要 癌症病因学。 拟议的项目将探讨 RAD51B 与已确定的关系 通过进一步表征 RAD51B-RAD51C 相互作用来实现复杂的合作伙伴。 其他研究将通过测试确定 RAD51B 的新型结合伙伴 用于 RAD51B 与 BRCA1 和 BRCA2 的特定相互作用。最近的几个 研究试图描述乳房之间的相互作用 使用免疫细胞化学技术的癌症相关基因产物。 HsRAD51 和 BRCA1 已被证明共定位于恶性乳腺细胞的核灶中 线。拟议的项目将进一步了解 RAD51B 的作用 通过检查 RAD51B 来研究涉及基因组稳定性和重组的途径 在 DNA 损伤之前和之后这些细胞结构中都存在。这 RAD51B 与已确定的蛋白质伴侣的关系将由 这些蛋白质在正常和恶性乳腺细胞系中的定位 减数分裂联会复合体。最近的研究表明 RAD51B 是损伤 正常和恶性乳腺癌中 RAD51B 的诱导细胞和缺陷细胞 将探索用这些药物处理的细胞系。这些研究将有助于 识别与 RAD51B 相互作用的蛋白质因子，从而提供见解 研究该蛋白质的生物学作用及其与乳腺癌的假定联系。