Bollé Sarune, Koc Elisa, Saiardi Adolfo, Juhran Lisa, Walla Eva, Fleig Ursula, Alcázar-Román Abel
Eukaryotic Microbiology, Department of Biology, Heinrich-Heine-University, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower St., London WC1E 6BT, UK.
Biomolecules. 2025 Sep 18;15(9):1331. doi: 10.3390/biom15091331.
Chromosome transmission fidelity is vital for organism fitness. Yet, extrinsic and intrinsic changes can affect this process, leading to aneuploidy, the loss/gain of chromosomes, which is a hallmark of cancer. Here, using a haploid fission yeast strain with a segmental aneuploidy, we assayed genome stability under different temperatures and altered gene dosage. We find that genome stability is temperature-dependent and is unexpectedly modulated by intracellular levels of inorganic polyphosphate polymers (polyP). The gene, encoding a subunit of the polyP-generating VTC complex, is present twice due to the segmental aneuploidy resulting in a gene-dosage-coupled increase in polyP. Using strains with different amounts of polyP, we find a direct negative correlation between polyP and chromosome segregation fidelity. PolyP modulates the function of the conserved CCAN kinetochore subcomplex, as the abnormal growth phenotype caused by the mutant CCAN protein Fta2-291 was rescued in the absence of polyP, while extra polyP had the opposite effect. Importantly, this appears to occur in part by modulation of the nucleolin Gar2. Gar2 is the functional homolog of the Nsr1 protein, whose function is modulated by posttranslational polyP-mediated polyphosphorylation. Thus, polyP modulates genome stability, linking cellular metabolism to chromosome transmission fidelity.
染色体传递保真度对生物体的适应性至关重要。然而，外在和内在的变化会影响这一过程，导致非整倍体，即染色体的丢失/增加，这是癌症的一个标志。在这里，我们使用具有节段性非整倍体的单倍体裂殖酵母菌株，检测了不同温度和基因剂量改变情况下的基因组稳定性。我们发现，基因组稳定性取决于温度，并且意外地受到细胞内无机多聚磷酸盐聚合物（多聚P）水平的调节。由于节段性非整倍体，编码产生多聚P的VTC复合物亚基的基因存在两份，导致多聚P在基因剂量耦合作用下增加。使用具有不同多聚P含量的菌株，我们发现多聚P与染色体分离保真度之间存在直接的负相关。多聚P调节保守的着丝粒CCAN亚复合物的功能，因为在没有多聚P的情况下，突变的CCAN蛋白Fta2 - 291引起的异常生长表型得到了挽救，而额外的多聚P则产生相反的效果。重要的是，这似乎部分是通过调节核仁素Gar2来实现的。Gar2是Nsr1蛋白的功能同源物，其功能受到翻译后多聚P介导的多磷酸化作用的调节。因此，多聚P调节基因组稳定性，将细胞代谢与染色体传递保真度联系起来。
