Zell Joanna, Rota Sperti Francesco, Britton Sébastien, Monchaud David
Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB CNRS UMR 6302, UBFC Dijon France
Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS Toulouse France.
RSC Chem Biol. 2020 Sep 30;2(1):47-76. doi: 10.1039/d0cb00151a. eCollection 2021 Feb 1.
Damaging DNA is a current and efficient strategy to fight against cancer cell proliferation. Numerous mechanisms exist to counteract DNA damage, collectively referred to as the DNA damage response (DDR) and which are commonly dysregulated in cancer cells. Precise knowledge of these mechanisms is necessary to optimise chemotherapeutic DNA targeting. New research on DDR has uncovered a series of promising therapeutic targets, proteins and nucleic acids, with application notably an approach referred to as combination therapy or combinatorial synthetic lethality. In this review, we summarise the cornerstone discoveries which gave way to the DNA being considered as an anticancer target, and the manipulation of DDR pathways as a valuable anticancer strategy. We describe in detail the DDR signalling and repair pathways activated in response to DNA damage. We then summarise the current understanding of non-B DNA folds, such as G-quadruplexes and DNA junctions, when they are formed and why they can offer a more specific therapeutic target compared to that of canonical B-DNA. Finally, we merge these subjects to depict the new and highly promising chemotherapeutic strategy which combines enhanced-specificity DNA damaging and DDR targeting agents. This review thus highlights how chemical biology has given rise to significant scientific advances thanks to resolutely multidisciplinary research efforts combining molecular and cell biology, chemistry and biophysics. We aim to provide the non-specialist reader a gateway into this exciting field and the specialist reader with a new perspective on the latest results achieved and strategies devised.
破坏DNA是当前对抗癌细胞增殖的一种有效策略。存在多种机制来对抗DNA损伤，这些机制统称为DNA损伤反应（DDR），在癌细胞中通常失调。精确了解这些机制对于优化化疗DNA靶向至关重要。DDR的新研究发现了一系列有前景的治疗靶点、蛋白质和核酸，其应用尤其体现在一种称为联合治疗或组合合成致死性的方法中。在这篇综述中，我们总结了那些使DNA被视为抗癌靶点以及将DDR途径的调控作为一种有价值的抗癌策略的基石性发现。我们详细描述了响应DNA损伤而激活的DDR信号传导和修复途径。然后，我们总结了目前对非B型DNA折叠结构（如G-四链体和DNA连接）的理解，包括它们何时形成以及与典型B-DNA相比为何能提供更具特异性的治疗靶点。最后，我们将这些主题融合起来，描绘了一种新的、极具前景的化疗策略，该策略结合了增强特异性的DNA损伤剂和DDR靶向剂。因此，这篇综述突出了化学生物学如何通过分子和细胞生物学、化学和生物物理学相结合的坚决多学科研究努力，带来了重大的科学进展。我们旨在为非专业读者打开进入这个令人兴奋领域的大门，并为专业读者提供对最新取得的成果和设计的策略的新视角。
