Khamidullina Alvina I, Abramenko Yaroslav E, Bruter Alexandra V, Tatarskiy Victor V
Laboratory of Molecular Oncobiology, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, 119334 Moscow, Russia.
Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, 119334 Moscow, Russia.
Int J Mol Sci. 2024 Jan 19;25(2):1263. doi: 10.3390/ijms25021263.
Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision of replication for fast proliferation and increased genomic instability. To overcome the consequences of improper replication control, malignant cells frequently inactivate parts of their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other pathways which help to maintain replication fork stability (ATR-CHK1). This creates a dependency on the remaining DDR pathways, vulnerability to further destabilization of replication and synthetic lethality of DDR inhibitors with common oncogenic alterations such as mutations of , , , amplifications of , and others. The response to RS is normally limited by coordination of cell cycle, transcription and replication. Inhibition of WEE1 and PKMYT1 kinases, which prevent unscheduled mitosis entry, leads to fragility of under-replicated sites. Recent evidence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets-ATR, CHK1, PARP and their inhibitors.
复制应激（RS）是癌细胞的一种特征性状态，因为它们倾向于以复制的精确性换取快速增殖和增加的基因组不稳定性。为了克服复制控制不当的后果，恶性细胞经常使部分DNA损伤反应（DDR）途径（ATM-CHK2-p53途径）失活，同时依赖于其他有助于维持复制叉稳定性的途径（ATR-CHK1）。这就造成了对其余DDR途径的依赖、对复制进一步不稳定的易感性以及DDR抑制剂与常见致癌改变（如 、 、 突变、 、 扩增等）的合成致死性。对RS的反应通常受到细胞周期、转录和复制协调的限制。抑制WEE1和PKMYT1激酶（它们可防止细胞意外进入有丝分裂）会导致未充分复制位点的脆弱性。最近的证据还表明，抑制细胞周期蛋白依赖性激酶（CDK），如CDK4/6、CDK2、CDK8/19和CDK12/13，可通过破坏DNA修复和复制控制而导致RS。在此，我们综述了癌症中RS的主要原因以及主要治疗靶点——ATR、CHK1、PARP及其抑制剂。
