A ROLE OF RAD51B IN DNA REPAIR AND BREAST CARCINOGENESIS

本建议的长期目标是阐明 一个新发现的人类基因，RAD 51 B，乳腺癌相关基因 也就是乳腺癌序列同源性表明，RAD 51 B是 在功能上类似于HsRAD 51（人RAD 51）。HsRAD 51基因产物具有 最近被证明与p53，BRCA 1和BRCA 2蛋白相互作用。 破坏BRCA 1和BRCA 2肿瘤抑制基因的突变导致 家族性乳腺癌和卵巢癌此外，还发现了p53突变。 在家族性乳腺癌以及很大比例的其他癌症中。 这些研究表明HsRASD 51基因在乳腺肿瘤发生中的作用。 此外，最近的发现表明，RAD 51 B与HsRAD 51相关 在多蛋白复合物中通过其与另一HsRAD 51同源物的相互作用， RAD51C。通常，RAD 51蛋白家族在必需的途径中起作用。 对于基因组稳定性，并考虑到HsRAD 51-BRCA相互作用， RAD 51 B基因及其功能可能是了解乳腺癌的关键 癌症病因学 建议的项目将探讨RAD 51 B与确定的 通过进一步表征RAD 51 B-RAD 51 C相互作用来鉴定复杂的伴侣。 进一步的研究将通过测试来鉴定RAD 51 B的新结合伴侣。 RAD 51 B与BRCA 1和BRCA 2的特异性相互作用。最近的几 研究试图描述乳腺癌和乳腺癌之间的相互作用， 癌症相关基因产物的免疫细胞化学技术。HsRAD 51和 BRCA 1已显示在恶性乳腺细胞的核病灶中共定位 线拟议的项目将进一步了解RAD 51 B的作用 通过检测RAD 51 B， 在DNA损伤之前和之后的这些细胞结构中。的 RAD 51 B与鉴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，RAD 51 B是一种 正常和恶性乳腺癌中可诱导和缺乏RAD 51 B细胞 将探索用这些试剂处理的细胞系。这些研究将有助于 鉴定与RAD 51 B相互作用的蛋白质因子， 蛋白质的生物学作用及其与乳腺癌的假定联系。

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.