Genetically induced redox stress occurs in a yeast model for Roberts syndrome.
Genetically induced redox stress occurs in a yeast model for Roberts syndrome.
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DOI：
10.1093/g3journal/jkab426
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发表时间：
2022-02-04
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
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罗伯茨综合征（RBS）是一种多谱发育障碍，其特征是严重的肢体、颅面和器官异常，通常伴有智力障碍。RBS的遗传基础植根于从酵母（Eco 1/Ctf 7）到人类保守的必需N-乙酰基转移酶ESCO 2的功能丧失突变。ESCO 2/Eco 1调节许多影响染色质结构、染色体传递、基因表达和基因组修复的细胞过程。RBS的病因学仍然存在争议，目前的模型包括转录失调或有丝分裂失败。在这里，我们报告的证据支持一个新兴的模型植根于缺陷的DNA损伤反应。首先，结果表明，氧化还原应激在eco 1和凝聚因子酿酒酵母突变体细胞中升高。其次，我们提供的证据表明，Eco 1和凝聚因子是修复氧化性DNA损伤所必需的，因此Eco 1和凝聚素基因突变导致细胞活力降低和氧化应激反应中发生的DNA损伤检查点的超活化。此外，我们表明，ECO 1的突变仅足以诱导内源性氧化还原应激和敏感的突变细胞外源性遗传毒性的挑战。值得注意的是，抗氧化剂治疗使eco 1突变细胞对一系列DNA损伤剂脱敏，提高了调节细胞氧化还原状态可能是治疗RBS和携带ESCO 2突变的肿瘤的重要途径的可能性。
Roberts syndrome (RBS) is a multispectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities. The genetic basis of RBS is rooted in loss-of-function mutations in the essential N-acetyltransferase ESCO2 which is conserved from yeast (Eco1/Ctf7) to humans. ESCO2/Eco1 regulate many cellular processes that impact chromatin structure, chromosome transmission, gene expression, and repair of the genome. The etiology of RBS remains contentious with current models that include transcriptional dysregulation or mitotic failure. Here, we report evidence that supports an emerging model rooted in defective DNA damage responses. First, the results reveal that redox stress is elevated in both eco1 and cohesion factor Saccharomyces cerevisiae mutant cells. Second, we provide evidence that Eco1 and cohesion factors are required for the repair of oxidative DNA damage such that ECO1 and cohesin gene mutations result in reduced cell viability and hyperactivation of DNA damage checkpoints that occur in response to oxidative stress. Moreover, we show that mutation of ECO1 is solely sufficient to induce endogenous redox stress and sensitizes mutant cells to exogenous genotoxic challenges. Remarkably, antioxidant treatment desensitizes eco1 mutant cells to a range of DNA damaging agents, raising the possibility that modulating the cellular redox state may represent an important avenue of treatment for RBS and tumors that bear ESCO2 mutations.
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粘蛋白乙酰转移酶ECO1坐标RDNA复制和转录。
影响因子：
7.7
作者：
Lu, Shuai;Lee, Kenneth K.;Harris, Bethany;Xiong, Bo;Bose, Tania;Saraf, Anita;Hattem, Gaye;Florens, Laurence;Seidel, Chris;Gerton, Jennifer L.
通讯作者：
Gerton, Jennifer L.
粘着蛋白突变是合成的致命，并刺激Wnt信号传导。
影响因子：
7.7
作者：
Chin CV;Antony J;Ketharnathan S;Labudina A;Gimenez G;Parsons KM;He J;George AJ;Pallotta MM;Musio A;Braithwaite A;Guilford P;Hannan RD;Horsfield JA
通讯作者：
Horsfield JA
影响因子：
4.8
作者：
Antoniacci, LM;Kenna, MA;Skibbens, RV
通讯作者：
Skibbens, RV
影响因子：
2.4
作者：
Banerji R;Skibbens RV;Iovine MK
通讯作者：
Iovine MK
DOI：
10.1016/0165-1161(89)90049-6
发表时间：
1989-10-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
BURNS, MA;TOMKINS, DJ
通讯作者：
TOMKINS, DJ