European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Aging Cell. 2020 Feb;19(2):e13084. doi: 10.1111/acel.13084. Epub 2019 Dec 18.
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.
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，而未能做到这一点会导致基因组不稳定，这是癌症和衰老的标志。参与保护基因组稳定性的基因缺陷会导致几种人类早衰综合征，并且在不同的生物体中，从酵母到哺乳动物，都观察到与年龄相关的突变积累。然而，目前尚不清楚自发突变率是否会随着衰老而改变，以及特定途径是否对老年细胞的基因组维持很重要。我们开发了一种高通量复制粘贴方法，用于筛选在酵母复制性衰老过程中抑制自发突变积累的重要基因。我们发现了 13 个已知的突变抑制基因，以及 31 个与自发突变没有先前联系的基因，所有这些基因都独立于年龄起作用。重要的是，我们确定了 PEX19，它编码一种进化上保守的过氧化物酶体生物发生因子，作为一种特定于年龄的突变抑制基因。虽然野生型和 pex19Δ 年轻细胞具有相似的自发突变率，但缺乏 PEX19 的衰老细胞显示出更高的突变率。这一发现表明，功能正常的过氧化物酶体可能对特定于老年细胞的基因组完整性的保存很重要。
