Defective homologous recombination repair and carcinogenesis

有缺陷的同源重组修复和致癌作用

• 批准号: 12213088
• 负责人: MIYAGAWA Kiyoshi
• 金额: $ 32.45万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213088/
• 关键词: homologous recombination; genome instability; DNA repair; breast cancer; chromosomal aberration

A defect in homologous recombination repair has been implicated in carcinogenesis because hereditary breast cancer genes BRCA were shown to play an important role in homologous recombination repair. We have investigated a molecular mechanism of homologous recombination repair in human cells. Rad54B, a gene identified as a novel recombination repair gene, exhibits the double-strand DNA-dependent ATPase activity and is required for gene targeting in human cells. XRCC3, a member of Rad51 paralog, is required for homologous recombination via sister chromatids. Additionally, XRCC3 prevents DNA rereplication and endoreduplication, thereby ensuring chromosome integrity. The T241M variant, a genetic polymorphism implicated in cancer risk, exhibits intact recombination repair, but fails to prevent endoreduplication, suggesting that an increase in endoreduplication is associated with cancer risk. A similar phenotype is observed in a resolvase gene Mus81-deficient cells. This aberration is caused by Cyclin B/Cdc2 inhibition by Chk2 activation in response to DNA damage. Thus, the recombination machinery is tightly associated with DNA replication and cell-cycle regulation. This finding suggests that a defect in the DNA metabolic network induces chromosome instability.

由于遗传性乳腺癌基因BRCA在同源重组修复中起重要作用，因此同源重组修复缺陷与癌发生有关。我们研究了人类细胞中同源重组修复的分子机制。Rad 54 B是一个新的重组修复基因，具有双链DNA依赖的ATP酶活性，是人类细胞基因打靶所必需的。XRCC 3是Rad 51同源染色体的一个成员，是通过姐妹染色单体进行同源重组所必需的。此外，XRCC 3阻止DNA再复制和核内再复制，从而确保染色体的完整性。T241 M变体是一种与癌症风险有关的遗传多态性，表现出完整的重组修复，但未能阻止核内复制，这表明核内复制的增加与癌症风险有关。在解离酶基因Mus 81缺陷细胞中观察到类似的表型。这种畸变是由响应于DNA损伤的Chk 2活化的Cyclin B/Cdc 2抑制引起的。因此，重组机制与DNA复制和细胞周期调控密切相关。这一发现表明，DNA代谢网络的缺陷会导致染色体不稳定。

项目成果

Takahashi, T.: "Evident for RAD51L1/HMGIC fusion in the pathogenesis of uterine leiomyoma"Genes Chromosomes Cancer. 30(2). 196-201 (2001)

Takahashi, T.：“RAD51L1/HMGIC 融合​​在子宫肌瘤发病机制中的证据”基因染色体癌症。

Tanaka,K.: "A novel human Rad54 homologue, Rad54B, associates with Rad51"J.Biol.Chem.. 275(34). 26316-26321 (2000)

Tanaka,K.：“一种新的人类 Rad54 同源物 Rad54B，与 Rad51 相关”J.Biol.Chem.. 275(34)。

Human Rad54B is a double-stranded DNA-dependent ATPase and has biochemical properties different from its structural homolog in yeast, Tid1/Rdh54

人类 Rad54B 是一种双链 DNA 依赖性 ATP 酶，其生化特性不同于其在酵母中的结构同源物 Tid1/Rdh54

• 发表时间: 2002
• 期刊: Nucleic Acids Res. 30
• 作者: Tanaka;K.
• 通讯作者: K.

A role for RAD54B in homologous recombination in human cells

• DOI: 10.1093/emboj/21.1.175
• 发表时间: 2002-01-15
• 期刊: EMBO JOURNAL
• 影响因子: 11.4
• 作者: Miyagawa, K;Tsuruga, T;Tanaka, K
• 通讯作者: Tanaka, K

Deoxycytidyl transferase activity of the human REV1 protein is closely associated with the conserved polymerase domain

• DOI: 10.1074/jbc.m008082200
• 发表时间: 2001-05-04
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Masuda, Y;Takahashi, M;Kamiya, K
• 通讯作者: Kamiya, K