Science For Life Laboratory (SciLifeLab), Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, Sweden.
Dis Model Mech. 2024 Aug 1;17(8). doi: 10.1242/dmm.050775. Epub 2024 Aug 29.
The size and composition of the intracellular DNA precursor pool is integral to the maintenance of genome stability, and this relationship is fundamental to our understanding of cancer. Key aspects of carcinogenesis, including elevated mutation rates and induction of certain types of DNA damage in cancer cells, can be linked to disturbances in deoxynucleoside triphosphate (dNTP) pools. Furthermore, our approaches to treat cancer heavily exploit the metabolic interplay between the DNA and the dNTP pool, with a long-standing example being the use of antimetabolite-based cancer therapies, and this strategy continues to show promise with the development of new targeted therapies. In this Review, we compile the current knowledge on both the causes and consequences of dNTP pool perturbations in cancer cells, together with their impact on genome stability. We outline several outstanding questions remaining in the field, such as the role of dNTP catabolism in genome stability and the consequences of dNTP pool expansion. Importantly, we detail how our mechanistic understanding of these processes can be utilised with the aim of providing better informed treatment options to patients with cancer.
细胞内 DNA 前体池的大小和组成对于维持基因组稳定性至关重要，这种关系是我们理解癌症的基础。癌症发生的关键方面，包括突变率升高和诱导癌细胞中某些类型的 DNA 损伤，都可以与脱氧核苷三磷酸 (dNTP) 池的紊乱联系起来。此外，我们治疗癌症的方法在很大程度上利用了 DNA 和 dNTP 池之间的代谢相互作用，一个长期存在的例子是使用基于抗代谢物的癌症疗法，随着新的靶向治疗方法的发展，这种策略继续显示出前景。在这篇综述中，我们总结了目前关于癌细胞中 dNTP 池扰动的原因和后果的知识，以及它们对基因组稳定性的影响。我们概述了该领域仍存在的几个悬而未决的问题，例如 dNTP 分解代谢在基因组稳定性中的作用以及 dNTP 池扩张的后果。重要的是，我们详细说明了如何利用我们对这些过程的机制理解，旨在为癌症患者提供更明智的治疗选择。
