A genome-wide screen identifies genes that suppress the accumulation of spontaneous mutations in young and aged yeast cells.,Aging Cell

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A genome-wide screen identifies genes that suppress the accumulation of spontaneous mutations in young and aged yeast cells.
Aging Cell ( IF 8.0 ) Pub Date : 2019-12-18 , DOI: 10.1111/acel.13084
Daniele Novarina ₁ , Georges E Janssens ₁ , Koen Bokern ₁ , Tim Schut ₁ , Noor C van Oerle ₁ , Hinke G Kazemier ₁ , Liesbeth M Veenhoff ₁ , Michael Chang ₁

Affiliation

To ensure proper transmission of genetic information, cells need to preserve and faithfully replicate their genome, and failure to do so leads to genome instability, a hallmark of both cancer and aging. Defects in genes involved in guarding genome stability cause several human progeroid syndromes, and an age‐dependent accumulation of mutations has been observed in different organisms, from yeast to mammals. However, it is unclear whether the spontaneous mutation rate changes during aging and whether specific pathways are important for genome maintenance in old cells. We developed a high‐throughput replica‐pinning approach to screen for genes important to suppress the accumulation of spontaneous mutations during yeast replicative aging. We found 13 known mutation suppression genes, and 31 genes that had no previous link to spontaneous mutagenesis, and all acted independently of age. Importantly, we identified PEX19, encoding an evolutionarily conserved peroxisome biogenesis factor, as an age‐specific mutation suppression gene. While wild‐type and pex19Δ young cells have similar spontaneous mutation rates, aged cells lacking PEX19 display an elevated mutation rate. This finding suggests that functional peroxisomes may be important to preserve genome integrity specifically in old cells.

中文翻译：

全基因组筛选可识别抑制年轻和老化酵母细胞中自发突变积累的基因。

为了确保遗传信息的正确传递，细胞需要保存并忠实地复制其基因组，否则将导致基因组不稳定，这是癌症和衰老的标志。涉及保护基因组稳定性的基因缺陷会导致多种人类早衰综合症，并且从酵母到哺乳动物，在不同的生物体中都观察到了年龄依赖性的突变积累。然而，尚不清楚衰老过程中自发突变率是否发生变化，以及特定途径是否对旧细胞的基因组维持很重要。我们开发了一种高通量的复制固定方法，以筛选对抑制酵母复制衰老过程中自发突变积累起重要作用的基因。我们发现了13个已知的突变抑制基因和31个与自发诱变没有关联的基因，所有人的行为都与年龄无关。重要的是，我们确定了PEX19编码一种进化上保守的过氧化物酶体生物发生因子，作为年龄特异性突变抑制基因。尽管野生型和pex19Δ年轻细胞具有相似的自发突变率，但缺少PEX19的衰老细胞却显示出较高的突变率。该发现表明功能性过氧化物酶体对于特别是在老细胞中保持基因组完整性可能是重要的。

更新日期：2019-12-18

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