Department of Chemistry and Molecular Biology, Lundberg Laboratory, University of Gothenburg, P.O. Box 462, Göteborg, SE-405 30, Sweden.
Cell Biol Int. 2020 Feb;44(2):412-423. doi: 10.1002/cbin.11241. Epub 2019 Oct 2.
Genetic analysis has strongly implicated human FHIT (Fragile Histidine Triad) as a tumor suppressor gene, being mutated in a large proportion of early-stage cancers. The functions of the FHIT protein have, however, remained elusive. Here, we investigated aph1 , the fission yeast homolog of FHIT, for functions related to checkpoint control and oxidative metabolism. In sublethal concentrations of DNA damaging agents, aph1Δ mutants grew with a substantially shorter lag phase. In aph1Δ mutants carrying a hypomorphic allele of cds1 (the fission yeast homolog of Chk2), in addition, increased chromosome fragmentation and missegregation were found. We also found that under hypoxia or impaired electron transport function, the Aph1 protein level was strongly depressed. Previously, FHIT has been linked to regulation of the human 9-1-1 checkpoint complex constituted by Hus1, Rad1, and Rad9. In Schizosaccharomyces pombe, the levels of all three 9-1-1 proteins are all downregulated by hypoxia in similarity with Aph1. Moreover, deletion of the aph1 gene reduced the Rad1 protein level, indicating a direct relationship between these two proteins. We conclude that the fission yeast FHIT homolog has a role in modulating DNA damage checkpoint function, possibly through an effect on the 9-1-1 complex, and that this effect may be critical under conditions of limiting oxidative metabolism and reoxygenation.
遗传分析强烈表明人类 FHIT（脆性组氨酸三联体）是一种肿瘤抑制基因，在很大比例的早期癌症中发生突变。然而，FHIT 蛋白的功能仍然难以捉摸。在这里，我们研究了 FHIT 的裂殖酵母同源物 aph1，以研究其与检查点控制和氧化代谢相关的功能。在亚致死浓度的 DNA 损伤剂下，aph1Δ 突变体的生长具有明显缩短的迟滞期。此外，在携带 cds1（裂殖酵母 Chk2 同源物）的弱等位基因的 aph1Δ 突变体中，发现染色体片段化和错误分离增加。我们还发现，在缺氧或电子传递功能受损的情况下，Aph1 蛋白水平会强烈下降。此前，FHIT 与由 Hus1、Rad1 和 Rad9 组成的人类 9-1-1 检查点复合物的调节有关。在裂殖酵母中，与 Aph1 相似，所有三种 9-1-1 蛋白的水平在缺氧下都被下调。此外，aph1 基因的缺失降低了 Rad1 蛋白水平，表明这两种蛋白之间存在直接关系。我们得出结论，裂殖酵母 FHIT 同源物在调节 DNA 损伤检查点功能方面发挥作用，可能通过对 9-1-1 复合物的影响，并且在氧化代谢有限和再氧化的条件下，这种作用可能至关重要。
