Marešová Anna, Grulyová Michaela, Hradilová Miluše, Zemlianski Viacheslav, Princová Jarmila, Převorovský Martin
Department of Cell Biology, Faculty of Science, Charles University, Prague, Czechia.
Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia.
PLoS Genet. 2024 Dec 9;20(12):e1011509. doi: 10.1371/journal.pgen.1011509. eCollection 2024 Dec.
Within a eukaryotic cell, both lipid homeostasis and faithful cell cycle progression are meticulously orchestrated. The fission yeast Schizosaccharomyces pombe provides a powerful platform to study the intricate regulatory mechanisms governing these fundamental processes. In S. pombe, the Cbf11 and Mga2 proteins are transcriptional activators of non-sterol lipid metabolism genes, with Cbf11 also known as a cell cycle regulator. Despite sharing a common set of target genes, little was known about their functional relationship. This study reveals that Cbf11 and Mga2 function together in the same regulatory pathway, critical for both lipid metabolism and mitotic fidelity. Deletion of either gene results in a similar array of defects, including slow growth, dysregulated lipid homeostasis, impaired cell cycle progression (cut phenotype), abnormal cell morphology, perturbed transcriptomic and proteomic profiles, and compromised response to the stressors camptothecin and thiabendazole. Remarkably, the double deletion mutant does not exhibit a more severe phenotype compared to the single mutants. In addition, ChIP-nexus analysis reveals that both Cbf11 and Mga2 bind to nearly identical positions within the promoter regions of target genes. Interestingly, Mga2 binding appears to be dependent on the presence of Cbf11 and Cbf11 likely acts as a tether to DNA, while Mga2 is needed to activate the target genes. In addition, the study explores the distribution of Cbf11 and Mga2 homologs across fungi. The presence of both Cbf11 and Mga2 homologs in Basidiomycota contrasts with Ascomycota, which mostly lack Cbf11 but retain Mga2. This suggests an evolutionary rewiring of the regulatory circuitry governing lipid metabolism and mitotic fidelity. In conclusion, this study offers compelling support for Cbf11 and Mga2 functioning jointly to regulate lipid metabolism and mitotic fidelity in fission yeast.
在真核细胞内，脂质稳态和精确的细胞周期进程都受到精心调控。裂殖酵母粟酒裂殖酵母为研究调控这些基本过程的复杂机制提供了一个强大的平台。在粟酒裂殖酵母中，Cbf11和Mga2蛋白是非甾醇脂质代谢基因的转录激活因子，Cbf11也被认为是一种细胞周期调节因子。尽管它们有一组共同的靶基因，但对它们的功能关系却知之甚少。这项研究表明，Cbf11和Mga2在同一调控途径中共同发挥作用，这对脂质代谢和有丝分裂保真度都至关重要。删除任何一个基因都会导致一系列类似的缺陷，包括生长缓慢、脂质稳态失调、细胞周期进程受损（切割表型）、细胞形态异常、转录组和蛋白质组图谱紊乱，以及对喜树碱和噻苯达唑等应激源的反应受损。值得注意的是，与单突变体相比，双缺失突变体并没有表现出更严重的表型。此外，ChIP-nexus分析表明，Cbf11和Mga2都结合在靶基因启动子区域内几乎相同的位置。有趣的是，Mga2的结合似乎依赖于Cbf11的存在，Cbf11可能作为与DNA的连接物，而Mga2则需要激活靶基因。此外，该研究还探索了Cbf11和Mga2同源物在真菌中的分布。担子菌门中同时存在Cbf11和Mga2同源物，而子囊菌门则大多缺乏Cbf11，但保留了Mga2。这表明在脂质代谢和有丝分裂保真度调控电路上存在进化重排。总之，这项研究为Cbf11和Mga2在裂殖酵母中共同调节脂质代谢和有丝分裂保真度提供了有力支持。
