Werner and Bloom helicases are involved in DNA repair in a complementary fashion
Werner and Bloom helicases are involved in DNA repair in a complementary fashion
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DOI：
10.1038/sj.onc.1205143
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发表时间：
2002-01-31
期刊：
影响因子：
8
通讯作者：
Matsumoto, T
中科院分区：
文献类型：
--
作者：
Imamura, O;Fujita, K;Matsumoto, T
维尔纳综合征（WS）是一种以过早衰老为特征的隐性疾病。布卢姆综合征（BS）是一种隐性疾病，其特征是身材矮小和免疫缺陷。这两种综合征的共同特征是基因组不稳定导致肿瘤发生。引起 WS 和 BS 的 WRN 和 BLM 基因编码与 RecQ 解旋酶密切相关的蛋白质。我们在鸡 B 细胞系 DT40 中产生了 WRN-/-、BLM-/- 和 WRN-/-/BLM-/- 突变体。 WRN-/-细胞对基因毒性剂（例如4-硝基喹啉1-氧化物、喜树碱和甲磺酸甲酯）表现出超敏反应。他们还显示外源 DNA 的目标整合率增加了三倍，但姐妹染色单体交换 (SCE) 频率却没有增加。 BLM-/- 细胞对基因毒性剂和紫外线 (UV) 表现出超敏感性，此外，目标整合率增加了 10 倍，SCE 频率增加了 11 倍。在WRN-/-/BLM-/-细胞中，观察到对基因毒性剂的超敏性协同增加，而与单一突变体相比，SCE频率和靶向整合率均部分降低。当在S后期至G(2)期用紫外线照射时，WRN-/-/BLM-/-细胞的染色体畸变也协同增加。这些结果表明 WRN 和 BLM 可能以互补的方式参与 DNA 修复。
Werner syndrome (WS) is a recessive disorder characterized by premature senescence. Bloom syndrome (BS) is a recessive disorder characterized by short stature and immunodeficiency. A common characteristic of both syndromes is genomic instability leading to tumorigenesis. WRN and BLM genes causing WS and BS, encode proteins that are closely related to the RecQ helicase. We produced WRN-/-, BLM-/- and WRN-/-/BLM-/- mutants in the chicken B-cell line DT40. WRN-/- cells showed hypersensitivities to genotoxic agents, such as 4-nitroquinoline 1-oxide, camptothecin and methyl methanesulfonate. They also showed a threefold increase in targeted integration rate of exogenous DNAs, but not in sister chromatid exchange (SCE) frequency. BLM-/- cells showed hypersensitivities to the genotoxic agents as well as ultraviolet (UV) light, in addition to a 10-fold increase in targeted integration rate and an 11-fold increase in SCE frequency. In WRN-/-/BLM-/- cells, synergistically increased hypersensitivities to the genotoxic agents were observed whereas both SCE frequencies and targeted integration rates were partially diminished compared to the single mutants. Chromosomal aberrations were also synergistically increased in WRN-/-/ BLM-/- cells when irradiated with UV light in late S to G(2) phases. These results suggest that both WRN and BLM may be involved in DNA repair in a complementary fashion.