文章：

参与DNA修复的DNA解旋酶及其在癌症中的作用

DNA helicases involved in DNA repair and their roles in cancer

原文发布日期：2013-07-11

DOI: 10.1038/nrc3560

类型: Review Article

开放获取: 否

要点：

1. Helicase-dependent DNA damage response and repair mechanisms help cells to cope with endogenous or exogenous stress to prevent chromosomal instability and maintain cellular homeostasis.
2. Inactivating mutations in DNA helicase genes are linked to genetic disorders that are frequently associated with various cancers. However, the expression of many DNA helicases is upregulated in transformed or neoplastic cells and tissues and is required for cancer cell proliferation or resistance to DNA damage imposed by chemotherapies.
3. The RecQ and iron-sulphur (Fe-S) families of DNA helicases have prominent roles in the maintenance of genomic stability through their catalytic functions and protein interactions in telomere maintenance and DNA repair pathways including nucleotide-excision repair (NER), homologous recombination (HR)-mediated repair of double-strand breaks (DSBs), interstrand crosslink (ICL) repair, and base-excision repair (BER).
4. Specialized DNA helicases efficiently unwind G-quadruplex (G4) DNA and other forms of alternative DNA structures such as telomeric displacement loops (T-loops). Emerging evidence suggests that DNA helicases that unwind non-conventional DNA structures have important roles in the replication or repair of telomeres.
5. Replication forks in rapidly dividing cancer cells are likely to encounter DNA lesions that perturb fork progression. Evidence suggests that certain DNA helicases help cells to cope with replicative lesions by remodelling the fork, restoring the integrity of broken replication forks, or having a role in the signalling mechanism for the intra-S-phase checkpoint.
6. Elevated expression of DNA helicases in rapidly proliferating cells and tumours suggests that they have a role in resistance to DNA-damaging agents and may represent good biomarkers for response to chemotherapies.
7. High-throughput screening of chemical libraries may prove to be beneficial for the discovery of small molecules that modulate helicase function in vivo. Such compounds may be useful in synthetic lethal approaches used in anticancer strategies that target tumours with existing DNA repair deficiencies.

要点翻译：

1. 解酶依赖性DNA损伤应答与修复机制协助细胞应对内源性或外源性应激，从而预防染色体不稳定性并维持细胞稳态。
2. DNA解旋酶基因的失活突变与遗传性疾病相关，这类疾病常伴随多种癌症发生。然而在转化细胞或肿瘤细胞与组织中，多种DNA解旋酶的表达却出现上调，这些解旋酶对癌细胞增殖或化疗引发的DNA损伤抵抗至关重要。
3. RecQ和铁硫簇（Fe-S）家族的DNA解旋酶通过其催化功能及在端粒维护中的蛋白相互作用，在核苷酸切除修复（NER）、同源重组（HR）介导的双链断裂（DSBs）修复、链间交联（ICL）修复及碱基切除修复（BER）等DNA修复通路中发挥重要作用，从而维持基因组稳定性。
4. 特异性DNA解旋酶能有效解开G-四链体（G4）DNA及端粒置换环（T环）等非经典DNA结构。新近证据表明，这些解旋酶在端粒复制或修复过程中具有重要作用。
5. 在快速分裂的癌细胞中，复制叉易遭遇阻碍其进展的DNA损伤。研究表明特定DNA解旋酶通过重塑复制叉、恢复断裂复制叉的完整性，或参与S期内检查点的信号传导机制，帮助细胞应对复制性损伤。
6. DNA解旋酶在快速增殖细胞和肿瘤组织中的高表达提示其参与抵抗DNA损伤剂的过程，并可能成为化疗疗效的良好生物标志物。
7. 对化学库进行高通量筛选或有助于发现调控体内解旋酶功能的小分子化合物。此类化合物在针对已有DNA修复缺陷肿瘤的抗癌策略中，可用于合成致死疗法。

英文摘要：

Helicases have major roles in genome maintenance by unwinding structured nucleic acids. Their prominence is marked by various cancers and genetic disorders that are linked to helicase defects. Although considerable effort has been made to understand the functions of DNA helicases that are important for genomic stability and cellular homeostasis, the complexity of the DNA damage response leaves us with unanswered questions regarding how helicase-dependent DNA repair pathways are regulated and coordinated with cell cycle checkpoints. Further studies may open the door to targeting helicases in order to improve cancer treatments based on DNA-damaging chemotherapy or radiation.

摘要翻译： 

解旋酶通过解开结构化核酸在基因组维护中发挥重要作用。其重要性体现在多种癌症和遗传疾病与解旋酶缺陷相关。尽管人们已投入大量努力以理解对基因组稳定性和细胞稳态至关重要的DNA解旋酶功能，但DNA损伤应答的复杂性仍使我们面临未解之谜：解旋酶依赖的DNA修复通路如何被调控，并与细胞周期检查点协调。进一步研究或将为靶向解旋酶铺平道路，从而优化基于DNA损伤化疗或放疗的癌症治疗。

原文链接：

DNA helicases involved in DNA repair and their roles in cancer