Cellular Responses to Widespread DNA Replication Stress.
Cellular Responses to Widespread DNA Replication Stress.
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DOI：
10.3390/ijms242316903
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发表时间：
2023-11-29
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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几乎所有类型的DNA损伤都会阻断复制型DNA聚合酶。由此产生的DNA复制压力威胁到基因组的稳定性。DNA复制应激也是由核苷酸库、DNA聚合酶抑制剂和难以复制的DNA序列或结构的耗尽引起的。复制应激触发复杂的细胞反应，包括细胞周期停滞，复制叉崩溃到一端DNA双链断裂，诱导DNA修复和过度损伤后的程序性细胞死亡。由特定结构引起的复制应力（例如，形成G-四链体的富含G的序列）是局部的，但发生在每次细胞分裂的S期。本文综述了细胞对广泛应激的反应，如随机DNA损伤、DNA聚合酶抑制/核苷酸库耗竭和R环。另一种形式的全局复制应激见于癌细胞中，称为致癌应激，反映了复制起点激发和/或复制叉进展失调。复制应激反应通常在癌细胞中失调，这也有助于持续的基因组不稳定性，从而推动癌症进展。核酸酶在复制应激反应中起关键作用，包括MUS 81、EEPD 1、Metnase、CtIP、MRE 11、EXO 1、DNA 2-BLM、SLX 1-SLX 4、XPF-ERCC 1-SLX 4、Artemis、XPG、FEN 1和TATDN 2。这些核酸酶中的几种在应激复制叉处切割分支DNA结构以促进这些叉的修复和重新启动。我们最近定义了EEPD 1在氧化DNA损伤后重新启动应激复制叉中的作用，以及TATDN 2在减轻BRCA 1缺陷细胞中R环积累引起的复制应激中的作用。我们还讨论了对全基因组复制应激的生物学反应的见解如何为利用复制应激反应因子之间的合成致死关系的新型癌症治疗策略提供信息。
Replicative DNA polymerases are blocked by nearly all types of DNA damage. The resulting DNA replication stress threatens genome stability. DNA replication stress is also caused by depletion of nucleotide pools, DNA polymerase inhibitors, and DNA sequences or structures that are difficult to replicate. Replication stress triggers complex cellular responses that include cell cycle arrest, replication fork collapse to one-ended DNA double-strand breaks, induction of DNA repair, and programmed cell death after excessive damage. Replication stress caused by specific structures (e.g., G-rich sequences that form G-quadruplexes) is localized but occurs during the S phase of every cell division. This review focuses on cellular responses to widespread stress such as that caused by random DNA damage, DNA polymerase inhibition/nucleotide pool depletion, and R-loops. Another form of global replication stress is seen in cancer cells and is termed oncogenic stress, reflecting dysregulated replication origin firing and/or replication fork progression. Replication stress responses are often dysregulated in cancer cells, and this too contributes to ongoing genome instability that can drive cancer progression. Nucleases play critical roles in replication stress responses, including MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, FEN1, and TATDN2. Several of these nucleases cleave branched DNA structures at stressed replication forks to promote repair and restart of these forks. We recently defined roles for EEPD1 in restarting stressed replication forks after oxidative DNA damage, and for TATDN2 in mitigating replication stress caused by R-loop accumulation in BRCA1-defective cells. We also discuss how insights into biological responses to genome-wide replication stress can inform novel cancer treatment strategies that exploit synthetic lethal relationships among replication stress response factors.
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