Loss of Elongation-Like Factor 1 Spontaneously Induces Diverse, RNase H-Related Suppressor Mutations in Schizosaccharomyces pombe.
Loss of Elongation-Like Factor 1 Spontaneously Induces Diverse, RNase H-Related Suppressor Mutations in Schizosaccharomyces pombe.
复制标题
DOI：
10.1534/genetics.118.301055
复制
发表时间：
2018-08
期刊：
影响因子：
3.3
通讯作者：
Zhang K
中科院分区：
文献类型：
--
作者：
Marayati BF;Drayton AL;Tucker JF;Huckabee RH;Anderson AM;Pease JB;Zeyl CW;Zhang K
一个健康的个体可能携带一种有害的遗传特征，这种特征被另一种基因突变所掩盖。这种抑制性遗传相互作用，即突变等位基因部分或完全恢复特定突变体的适应性缺陷，往往发生在具有有限功能连接的基因之间。在这里，我们研究了粟酒裂殖酵母的自我恢复表型，介导的抑制性遗传相互作用，可以在细胞培养过程中放大。没有Elf 1（AAA+家族ATP酶）的细胞最初有严重的生长缺陷，但通过获得抑制突变，生长速度很快恢复到野生型菌株的水平。elf 1 Δ细胞在细胞核内积累RNA，并显示基因组不稳定性的影响，如对DNA损伤的敏感性，滞后染色体的发生率增加和微染色体丢失。值得注意的是，在elf 1 Δ细胞中，当RNase H活性被消除时，表型恢复率进一步提高，而在RNase H1过表达时，表型恢复率显著降低，这表明Elf 1相关基因组不稳定性的丧失可以通过RNase H活性来解决，这可能是通过消除由RNA核积累引起的潜在致突变DNA-RNA杂合体来解决的。使用全基因组测序，我们绘制了一些一致的elf 1 Δ抑制因子，包括突变的Cue 2，Rp 12702和SPBPJ4664.02，表明Elf 1和这些蛋白质之间以前未知的功能连接。我们的研究结果描述了一种机制，通过这种机制，携带导致适应性缺陷和基因组不稳定的突变的细胞可以通过快速获得抑制因子来加速其种群的适应性恢复。我们认为，这种机制可能普遍适用于大规模培养中的所有微生物。
A healthy individual may carry a detrimental genetic trait that is masked by another genetic mutation. Such suppressive genetic interactions, in which a mutant allele either partially or completely restores the fitness defect of a particular mutant, tend to occur between genes that have a confined functional connection. Here we investigate a self-recovery phenotype in Schizosaccharomyces pombe, mediated by suppressive genetic interactions that can be amplified during cell culture. Cells without Elf1, an AAA+ family ATPase, have severe growth defects initially, but quickly recover growth rates near to those of wild-type strains by acquiring suppressor mutations. elf1Δ cells accumulate RNAs within the nucleus and display effects of genome instability such as sensitivity to DNA damage, increased incidence of lagging chromosomes, and mini-chromosome loss. Notably, the rate of phenotypic recovery was further enhanced in elf1Δ cells when RNase H activities were abolished and significantly reduced upon overexpression of RNase H1, suggesting that loss of Elf1-related genome instability can be resolved by RNase H activities, likely through eliminating the potentially mutagenic DNA–RNA hybrids caused by RNA nuclear accumulation. Using whole genome sequencing, we mapped a few consistent suppressors of elf1Δ including mutated Cue2, Rpl2702, and SPBPJ4664.02, suggesting previously unknown functional connections between Elf1 and these proteins. Our findings describe a mechanism by which cells bearing mutations that cause fitness defects and genome instability may accelerate the fitness recovery of their population through quickly acquiring suppressors. We propose that this mechanism may be universally applicable to all microorganisms in large-population cultures.