Identification of genetic factors involved in the human genomic instability

鉴定与人类基因组不稳定性有关的遗传因素

• 批准号: 08680694
• 负责人: WADA Morimasa
• 金额: $ 1.54万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08680694/
• 关键词: genomic instability; tumor; genetic diseases; Fragile X syndrome; repeat; yeast artificial chromosome; topoisomerasell; color blinedness; セントロメア; サッカロミセス

Genomic instability has been shown to be involved in the tumor development and the genetic diseases such as Fragile X syndrome and Hungtinton disease. However, genetic factors and mechanisms participating in the genomic instability has not been identified. We focused on the factors involved in the instability of repeat sequences, because all genomic region showing instability contain repeat sequences. We have isolated yeast mutants which suppress the instability of yeast artificial chromosome carrying human direct repeat sequence. We have then isolated yeast genomic clones which suppress the mutant phenotype. Finally, we identified A-stretch sequence in one clone and topoisomerasell sequence in another clone, suggesting these two sequences might be involved in the instability of repeat sequences in human genome.

基因组不稳定性已被证明参与肿瘤发育以及诸如脆弱X综合征和Hungtinton疾病之类的遗传疾病。但是，尚未确定参与基因组不稳定性的遗传因素和机制。我们专注于重复序列不稳定性的因素，因为所有显示不稳定性的基因组区域都包含重复序列。我们有孤立的酵母突变体，可抑制携带人造直接重复序列的酵母人工染色体的不稳定性。然后，我们分离了抑制突变表型的酵母基因组克隆。最后，我们在另一个克隆中鉴定了一个克隆和拓扑异构贝尔序列中的a牵引序列，这表明这两个序列可能与人类基因组重复序列的不稳定性有关。

项目成果

H.Kusaba: "Functional expression of yeast artificial chromosome (YAC)-human multidrug resistance genesin mouse cells." Genome Research. 5. 245-258 (1995)

H.Kusaba：“酵母人工染色体（YAC）-人类多药耐药基因在小鼠细胞中的功能表达。”

Taniguchi,K.: "A human canalicular multispecific or ganic anion transporter (cMOAT) gene is overexpressed in cisplatin resistant human cancer cell lines with decreased drug accumulation." Cancer Research. 56. 4124-4129 (1996)

Taniguchi,K.：“人小管多特异性或有机阴离子转运蛋白 (cMOAT) 基因在顺铂耐药的人癌细胞系中过度表达，药物蓄积减少。”

Taniguchi,K.: "Drug-induced down-regulation of topoisomeraase 1 in human epidermoid cancer cells resistant to saintopin and camptothecins." Cancer Research. 56. 2348-2354 (1996)

Taniguchi, K.：“药物诱导对圣托品和喜树碱耐药的人表皮样癌细胞中拓扑异构酶 1 的下调。”

T.Kubo: "DNA topoisomer as ella gene expression unde transcriptional control in etoposide/teniposide resistant human cancer cells." Cancer Res.55. 3860-3864 (1995)

T.Kubo：“在依托泊苷/替尼泊苷耐药的人类癌细胞中，DNA 拓扑异构体作为 ella 基因表达在转录控制下。”

Wada, M., et al.: "Mutation in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome." Hum.Mol.Genetics. 7. 203-207 (1998)

Wada, M., 等人：“高胆红素血症 II/Dubin-Johnson 综合征患者的小管多特异性有机阴离子转运蛋白 (cMOAT) 基因（一种新型 ABC 转运蛋白）发生突变。”