Evolutionarily conserved genetic interactions with budding and fission yeast MutS identify orthologous relationships in mismatch repair-deficient cancer cells.
Evolutionarily conserved genetic interactions with budding and fission yeast MutS identify orthologous relationships in mismatch repair-deficient cancer cells.
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DOI：
10.1186/s13073-014-0068-4
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发表时间：
2014
期刊：
影响因子：
12.3
通讯作者：
Edelmann W
中科院分区：
文献类型：
--
作者：
Tosti E;Katakowski JA;Schaetzlein S;Kim HS;Ryan CJ;Shales M;Roguev A;Krogan NJ;Palliser D;Keogh MC;Edelmann W
进化上保守的DNA错配修复（MMR）系统可以纠正错误复制过程中产生的碱基替换和插入-删除突变。许多MMR因子的突变或失活极易导致癌症，而由此产生的肿瘤通常对标准化疗具有耐药性。开发靶向治疗的一个新方向是利用合成遗传相互作用，其中同时失去两个其他非必要因素导致细胞适应性降低或死亡。在人类细胞中进行高通量筛选，直接识别疾病相关基因的相互作用物，现在已经很普遍，但通常需要大量的个案优化。在这里，我们询问是否保守的遗传相互作用（CGIs）与MMR基因从两个进化遥远的酵母菌种（酿酒酵母和pombe裂糖酵母菌）可以预测同源遗传关系在高等真核生物。利用高通量筛选鉴定了裂变酵母MutSα和MutSβ异源二聚体亚基（msh2Δ， msh3Δ， msh6Δ）的遗传相互作用谱。在出芽酵母中直接分析了与MutSβ （msh2Δ/msh3Δ）负相互作用的筛选物，并在msh2缺失和msh2成熟的人细胞中通过RNA干扰/药物处理进一步检测了与sumo -蛋白酶Ulp2的CGI。这项研究发现了MutSα和MutSβ的不同遗传谱，并支持后者在重组DNA修复中的作用。在这两种酵母中，与msh2Δ/msh3Δ的同源遗传相互作用约有28%是保守的，这一程度与这些物种的全球趋势一致。此外，出芽/裂变酵母msh2和sumo蛋白酶Ulp2之间的CGI在人类细胞（msh2 /SENP6）中得以维持，并被Olaparib（一种诱导单链DNA断裂积累的PARP抑制剂）增强。这表明SENP6是治疗mmr缺陷癌症的一个有希望的新靶点。我们的发现证明了利用进化距离在可处理的低等真核生物中预测高等真核生物的同源遗传关系的效用。此外，我们对一个关键DNA修复复合体的基因组维持功能提供了新的见解，并提出了一种有希望的靶向治疗MMR缺陷肿瘤的方法。本文的在线版本（doi:10.1186/ s130773 -014-0068-4）包含补充材料，授权用户可以使用。
The evolutionarily conserved DNA mismatch repair (MMR) system corrects base-substitution and insertion-deletion mutations generated during erroneous replication. The mutation or inactivation of many MMR factors strongly predisposes to cancer, where the resulting tumors often display resistance to standard chemotherapeutics. A new direction to develop targeted therapies is the harnessing of synthetic genetic interactions, where the simultaneous loss of two otherwise non-essential factors leads to reduced cell fitness or death. High-throughput screening in human cells to directly identify such interactors for disease-relevant genes is now widespread, but often requires extensive case-by-case optimization. Here we asked if conserved genetic interactors (CGIs) with MMR genes from two evolutionary distant yeast species (Saccharomyces cerevisiae and Schizosaccharomyzes pombe) can predict orthologous genetic relationships in higher eukaryotes. High-throughput screening was used to identify genetic interaction profiles for the MutSα and MutSβ heterodimer subunits (msh2Δ, msh3Δ, msh6Δ) of fission yeast. Selected negative interactors with MutSβ (msh2Δ/msh3Δ) were directly analyzed in budding yeast, and the CGI with SUMO-protease Ulp2 further examined after RNA interference/drug treatment in MSH2-deficient and -proficient human cells. This study identified distinct genetic profiles for MutSα and MutSβ, and supports a role for the latter in recombinatorial DNA repair. Approximately 28% of orthologous genetic interactions with msh2Δ/msh3Δ are conserved in both yeasts, a degree consistent with global trends across these species. Further, the CGI between budding/fission yeast msh2 and SUMO-protease Ulp2 is maintained in human cells (MSH2/SENP6), and enhanced by Olaparib, a PARP inhibitor that induces the accumulation of single-strand DNA breaks. This identifies SENP6 as a promising new target for the treatment of MMR-deficient cancers. Our findings demonstrate the utility of employing evolutionary distance in tractable lower eukaryotes to predict orthologous genetic relationships in higher eukaryotes. Moreover, we provide novel insights into the genome maintenance functions of a critical DNA repair complex and propose a promising targeted treatment for MMR deficient tumors. The online version of this article (doi:10.1186/s13073-014-0068-4) contains supplementary material, which is available to authorized users.
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影响因子：
--
作者：
Albrow VE;Ponder EL;Fasci D;Békés M;Deu E;Salvesen GS;Bogyo M
通讯作者：
Bogyo M
影响因子：
64.5
作者：
Frost A;Elgort MG;Brandman O;Ives C;Collins SR;Miller-Vedam L;Weibezahn J;Hein MY;Poser I;Mann M;Hyman AA;Weissman JS
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120.1
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影响因子：
16
作者：
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van Attikum H
影响因子：
5.4
作者：
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通讯作者：
Kerscher O