ROLE FOR 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: 6041901
• 负责人: Joanna S Albala
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6041901
• 关键词: DNA repair; brca gene; breast neoplasms; chemical carcinogen; chemical carcinogenesis; cis platinum compound; genetic recombination; intermolecular interaction; ionizing radiation; neoplasm /cancer genetics; radiation carcinogen; radiation carcinogenesis; tissue /cell culture; tumor suppressor genes; 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 R4AD51B 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 HsRAD51 gene in breast tumorigenesis. Furthermore, recent discoveries indicate that RAB51B associates with HsRAD51 within a multi-protein complex by its interaction with another HsRAD51 homolog, RAD51C. In 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 identified 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 been shown to co-localize in nuclear foci in a malignant breast cell line. The proposed project will further the understanding 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 a 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 are sensitive to both ionizing radiation and the chemotherapeutic agent, cisplatin. Expression of READ51B 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.

这项提案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，因此，乳腺癌的关系。序列同源性表明R4 AD 51 B在功能上类似于HsRAD 51（人RAD 51）。HsRAD 51基因产物最近被证明与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，在家族性乳腺癌以及大部分其他癌症中发现了p53突变。这些研究表明HsRAD 51基因在乳腺肿瘤发生中的作用。此外，最近的发现表明，RAB 51 B通过与另一种HsRAD 51同源物RAD 51 C相互作用而与HsRAD 51在多蛋白复合物中缔合。在HsRAD 51-BRCA相互作用中，RAD 51 B基因及其功能的研究对于理解乳腺癌的病因可能是至关重要的。拟议的项目将通过进一步表征RAD 51 B-RAD 51 C相互作用来探索RAD 51 B与已确定的复杂伙伴的关系。其他研究将通过检测RAD 51 B与BRCA 1和BRCA 2的特异性相互作用来鉴定RAD 51 B的新结合伴侣。最近的几项研究试图用免疫细胞化学技术来描述乳腺癌相关基因产物的相互作用。HsRAD 51和BRCA 1已显示在恶性乳腺细胞系的核病灶中共定位。拟议的项目将通过检查DNA损伤前后这些细胞结构中的RAD 51 B，进一步了解RAD 51 b在基因组稳定性和重组途径中的作用。将通过这些蛋白质在正常和恶性乳腺细胞系以及减数分裂联会复合体中的定位来检查RAD 51 B与已识别蛋白质伴侣的关系。最近的研究表明，RAD 51 B是损伤诱导型的，并且RAD 51 B缺陷的细胞对电离辐射和化疗剂顺铂都敏感。READ 51 B在用这些药剂处理的正常和恶性乳腺癌细胞系中的表达将被探索。这些研究将有助于确定与RAD 51 B相互作用的蛋白质因子，从而深入了解该蛋白质的生物学作用及其与乳腺癌的假定联系。

项目成果

Identification of chromatin-related protein interactions using protein microarrays.

使用蛋白质微阵列鉴定染色质相关蛋白质相互作用。

• DOI: 10.1002/pmic.200300593
• 发表时间: 2003
• 期刊: Proteomics
• 影响因子: 3.4
• 作者: Coleman,MatthewA;Miller,KristiA;Beernink,PeterT;Yoshikawa,DanielM;Albala,JoannaS
• 通讯作者: Albala,JoannaS