Hsp90 modulates CAG repeat instability in human cells
Hsp90 modulates CAG repeat instability in human cells
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DOI：
10.1007/s12192-010-0191-0
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发表时间：
2010-09-01
影响因子：
3.8
通讯作者：
Wilson, John H.
中科院分区：
文献类型：
--
作者：
Mittelman, David;Sykoudis, Kristen;Wilson, John H.
Hsp90 分子伴侣被认为是多种生物体进化的贡献者，它揭示了当伴侣因环境压力而偏离其正常功能时可产生戏剧性表型的神秘变异。此外，作为癌症药物靶标，Hsp90 抑制已被证明可使细胞对 DNA 损伤剂敏感，表明 Hsp90 在 DNA 修复中具有功能。在这里，我们探讨了 Hsp90 在调节核苷酸重复稳定性方面的潜在作用，在包括人类在内的许多物种中，核苷酸重复对蛋白质功能、形态和行为特征以及疾病产生微妙和定量的影响。我们报告说，人类细胞中 Hsp90 的损伤会导致 CAG 重复轨迹收缩十倍。重组酶 Rad51（Hsp90 的下游靶标）的抑制会导致重复不稳定性显着增加，这表明 Hsp90 启用的同源重组通常起到稳定 CAG 重复序列的作用。相比之下，Hsp90 抑制不会增加基因失活点突变的发生率。 Hsp90 调节重复序列长度的能力表明，伴侣除了暴露隐性变异之外，还可能通过诱导新的遗传变异来促进新表型的表达。
The Hsp90 molecular chaperone has been implicated as a contributor to evolution in several organisms by revealing cryptic variation that can yield dramatic phenotypes when the chaperone is diverted from its normal functions by environmental stress. In addition, as a cancer drug target, Hsp90 inhibition has been documented to sensitize cells to DNA-damaging agents, suggesting a function for Hsp90 in DNA repair. Here we explore the potential role of Hsp90 in modulating the stability of nucleotide repeats, which in a number of species, including humans, exert subtle and quantitative consequences for protein function, morphological and behavioral traits, and disease. We report that impairment of Hsp90 in human cells induces contractions of CAG repeat tracks by tenfold. Inhibition of the recombinase Rad51, a downstream target of Hsp90, induces a comparable increase in repeat instability, suggesting that Hsp90-enabled homologous recombination normally functions to stabilize CAG repeat tracts. By contrast, Hsp90 inhibition does not increase the rate of gene-inactivating point mutations. The capacity of Hsp90 to modulate repeat-tract lengths suggests that the chaperone, in addition to exposing cryptic variation, might facilitate the expression of new phenotypes through induction of novel genetic variation.