Roux Pierre, Salort Delphine, Xu Zhou
Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France.
Laboratoire de Mathématiques d'Orsay (LMO), Université Paris-Sud, Paris-Saclay, Orsay, France.
R Soc Open Sci. 2021 Aug 25;8(8):210460. doi: 10.1098/rsos.210460. eCollection 2021 Aug.
In response to DNA damage, efficient repair is essential for cell survival and genome integrity. In eukaryotes, the DNA damage checkpoint is a signalling pathway that coordinates this response and arrests the cell cycle to provide time for repair. However, when repair fails or when the damage is not repairable, cells can eventually bypass the DNA damage checkpoint and undergo cell division despite persistent damage, a process called adaptation to DNA damage. Interestingly, adaptation occurs with a delayed timing compared with repair and shows a large variation in time, two properties that may provide a survival advantage at the population level without interfering with repair. Here, we explore this idea by mathematically modelling cell survival in response to DNA damage and focusing on adaptation parameters. We find that the delayed adaptation timing indeed maximizes survival, but its heterogeneity is beneficial only in a fluctuating damage-inducing environment. Finally, we show that adaptation does not only contribute to survival but also to genome instability and mutations, which might represent another criterion for its selection throughout evolution. Overall, we propose that adaptation can act as a bet-hedging mechanism for cell survival in response to DNA damage.
响应DNA损伤时，高效修复对于细胞存活和基因组完整性至关重要。在真核生物中，DNA损伤检查点是一条信号通路，可协调这种反应并使细胞周期停滞，为修复提供时间。然而，当修复失败或损伤无法修复时，细胞最终可以绕过DNA损伤检查点，尽管存在持续性损伤仍进行细胞分裂，这一过程称为对DNA损伤的适应。有趣的是，与修复相比，适应发生的时间较晚，并且在时间上表现出很大的差异，这两个特性可能在不干扰修复的情况下在群体水平上提供生存优势。在这里，我们通过对响应DNA损伤的细胞存活进行数学建模并关注适应参数来探索这一观点。我们发现延迟的适应时间确实能使存活率最大化，但其异质性仅在波动的损伤诱导环境中才有益。最后，我们表明适应不仅有助于存活，还会导致基因组不稳定和突变，这可能是其在整个进化过程中被选择的另一个标准。总体而言，我们提出适应可以作为一种应对DNA损伤的细胞存活的风险对冲机制。
