WRN helicase defective in the premature aging disorder Werner syndrome genetically interacts with topoisomerase 3 and restores the top3 slow growth phenotype of sgs1 top3.
WRN helicase defective in the premature aging disorder Werner syndrome genetically interacts with topoisomerase 3 and restores the top3 slow growth phenotype of sgs1 top3.
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DOI：
10.18632/aging.100020
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发表时间：
2009-02-05
期刊：
影响因子：
--
通讯作者：
Brosh RM
中科院分区：
文献类型：
--
作者：
Aggarwal M;Brosh RM
沃纳综合征（WS）是一种以基因组不稳定为特征的早衰性疾病。 WS 中缺陷的 WRN 基因编码具有解旋酶和核酸外切酶活性的蛋白质，该蛋白质与 DNA 代谢中涉及的蛋白质相互作用。 为了了解其遗传功能，我们检查了人类 WRN 拯救与 sgs1（酿酒酵母中唯一的 RecQ 解旋酶）相关的表型的能力。 WRN 未能挽救 sgs1 对 DNA 损伤剂甲基磺酸盐或复制抑制剂羟基脲的敏感性，这表明人和酵母 RecQ 解旋酶的功能不同。 然而，sgs1 top3 中 WRN 的生理表达恢复了 top3 缓慢生长表型，而野生型或 sgs1 菌株没有观察到对生长的影响。 WRN 转化的 sgs1 top3 的缓慢生长与细胞核未分裂的大芽细胞数量的增加相关，表明 top3 晚期 S/G2 特征的细胞周期延迟得到恢复。 恢复 top3 生长表型在遗传上需要 WRN 解旋酶活性，而不是核酸外切酶活性，这证明了 WRN 催化活性的功能分离。 WRN 中自然发生的错义多态性会干扰解旋酶活性，从而消除了其恢复 top3 缓慢生长表型的能力。 讨论了 WRN 在遗传途径中对于抑制基因组不稳定性的重要作用。
Werner syndrome (WS) is a premature aging disorder characterized by genomic instability. The WRN gene defective in WS encodes a protein with both helicase and exonuclease activities that interacts with proteins implicated in DNA metabolism. To understand its genetic functions, we examined the ability of human WRN to rescue phenotypes associated with sgs1, the sole RecQ helicase in Saccharomyces cerevisiae. WRN failed to rescue sgs1 sensitivity to the DNA damaging agent methylmethane sulfonate or replication inhibitor hydroxyurea, suggesting divergent functions of human and yeast RecQ helicases. However, physiological expression of WRN in sgs1 top3 restored top3 slow growth phenotype, whereas no effect on growth was observed with wild-type or sgs1 strains. Slow growth of WRN-transformed sgs1 top3 correlated with an elevated population of large-budded cells with undivided nuclei, indicating restoration of cell cycle delay in late S/G2 characteristic of top3. WRN helicase but not exonuclease activity was genetically required for restoration of top3 growth phenotype, demonstrating separation of function of WRN catalytic activities. A naturally occurring missense polymorphism in WRN that interferes with helicase activity abolished its ability to restore top3 slow growth phenotype. Proposed roles of WRN in genetic pathways important for the suppression of genomic instability are discussed.
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