Nucleases and Co-Factors in DNA Replication Stress Responses.

DNA Pub Date : 2022-03-01 DOI:10.3390/dna2010006
Jac A Nickoloff, Neelam Sharma, Lynn Taylor, Sage J Allen, Robert Hromas
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Abstract

DNA replication stress is a constant threat that cells must manage to proliferate and maintain genome integrity. DNA replication stress responses, a subset of the broader DNA damage response (DDR), operate when the DNA replication machinery (replisome) is blocked or replication forks collapse during S phase. There are many sources of replication stress, such as DNA lesions caused by endogenous and exogenous agents including commonly used cancer therapeutics, and difficult-to-replicate DNA sequences comprising fragile sites, G-quadraplex DNA, hairpins at trinucleotide repeats, and telomeres. Replication stress is also a consequence of conflicts between opposing transcription and replication, and oncogenic stress which dysregulates replication origin firing and fork progression. Cells initially respond to replication stress by protecting blocked replisomes, but if the offending problem (e.g., DNA damage) is not bypassed or resolved in a timely manner, forks may be cleaved by nucleases, inducing a DNA double-strand break (DSB) and providing a means to accurately restart stalled forks via homologous recombination. However, DSBs pose their own risks to genome stability if left unrepaired or misrepaired. Here we focus on replication stress response systems, comprising DDR signaling, fork protection, and fork processing by nucleases that promote fork repair and restart. Replication stress nucleases include MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, and FEN1. Replication stress factors are important in cancer etiology as suppressors of genome instability associated with oncogenic mutations, and as potential cancer therapy targets to enhance the efficacy of chemo- and radiotherapeutics.

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DNA复制应激反应中的核酸酶和共因子。
DNA复制压力是一个持续的威胁,细胞必须设法增殖并保持基因组完整性。DNA复制应激反应是更广泛的DNA损伤反应(DDR)的一个子集,当DNA复制机制(复制子体)在S期被阻断或复制叉塌陷时,它就会发挥作用。复制应激有许多来源,如内源性和外源性因素引起的DNA损伤,包括常用的癌症治疗剂,以及难以复制的DNA序列,包括脆弱位点、G-quadraplex DNA、三核苷酸重复的发夹和端粒。复制应激也是反向转录和复制之间冲突的结果,以及失调复制起源发射和分叉进展的致癌应激。细胞最初通过保护被阻断的复制体来应对复制应激,但如果没有及时绕过或解决问题(例如DNA损伤),叉可能会被核酸酶切割,从而诱导DNA双链断裂(DSB),并通过同源重组提供准确重启停滞叉的手段。然而,如果未修复或修复不当,DSBs也会对基因组稳定性造成风险。在这里,我们重点关注复制应激反应系统,包括DDR信号、分叉保护和通过核酸酶进行的分叉处理,以促进分叉修复和重启。复制应激核酸酶包括MUS81、EEPD1、Metnase、CtIP、MRE11、EXO1、DNA2-BLM、SLX1-SLX4、XPF-ERCC1-SLX4,Artemis、XPG和FEN1。复制应激因子作为与致癌突变相关的基因组不稳定性的抑制剂,以及作为提高化疗和放射治疗效果的潜在癌症治疗靶点,在癌症病因中是重要的。
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