Natalino Mariana, Fumasoni Marco
Gulbenkian Institute for Molecular Medicine (GIMM), Lisbon, Portugal.
bioRxiv. 2024 Nov 1:2024.10.29.620637. doi: 10.1101/2024.10.29.620637.
Evolutionary repair refers to the compensatory evolution that follows perturbations in cellular processes. While evolutionary trajectories are often reproducible, other studies suggest they are shaped by genotype-by-environment (GxE) interactions. Here, we test the predictability of evolutionary repair in response to DNA replication stress-a severe perturbation impairing the conserved mechanisms of DNA synthesis, resulting in genetic instability. We conducted high-throughput experimental evolution on experiencing constitutive replication stress, grown under different glucose availabilities. We found that glucose levels impact the physiology and adaptation rate of replication stress mutants. However, the genetics of adaptation show remarkable robustness across environments. Recurrent mutations collectively recapitulated the fitness of evolved lines and are advantageous across macronutrient availability. We also identified a novel role of the mediator complex of RNA polymerase II in adaptation to replicative stress. Our results highlight the robustness and predictability of evolutionary repair mechanisms to DNA replication stress and provide new insights into the evolutionary aspects of genome stability, with potential implications for understanding cancer development.
进化修复是指细胞过程受到干扰后随之发生的补偿性进化。虽然进化轨迹通常具有可重复性，但其他研究表明，它们是由基因型与环境（GxE）相互作用塑造的。在这里，我们测试了进化修复对DNA复制应激（一种严重干扰DNA合成保守机制并导致基因不稳定的扰动）的可预测性。我们对在不同葡萄糖可用性条件下生长的经历组成型复制应激的[具体对象未提及]进行了高通量实验进化。我们发现葡萄糖水平会影响复制应激突变体的生理机能和适应率。然而，适应的遗传学在不同环境中表现出显著的稳健性。反复出现的突变共同概括了进化系的适应性，并且在大量营养素可用性方面具有优势。我们还确定了RNA聚合酶II的中介复合物在适应复制应激中的新作用。我们的结果突出了进化修复机制对DNA复制应激的稳健性和可预测性，并为基因组稳定性的进化方面提供了新见解，对理解癌症发展具有潜在意义。
