DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy.
DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy.
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DOI：
10.3389/fonc.2013.00113
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发表时间：
2013
影响因子：
4.7
通讯作者：
Iliakis G
中科院分区：
文献类型：
--
作者：
Mladenov E;Magin S;Soni A;Iliakis G
放射治疗在多种癌症的治疗中发挥着重要作用。除了放射剂量物理应用方面的创新之外，放射治疗还可能受益于利用正常细胞和肿瘤细胞之间放射反应差异的新方法。虽然电离辐射会诱发多种 DNA 损伤，包括碱基损伤和单链断裂，但 DNA 双链断裂 (DSB) 被广泛认为是不仅导致肿瘤细胞定向杀伤的损伤，而且还导致一般基因组不稳定性，从而导致正常细胞中继发性癌症的发展。同源重组修复 (HRR)、非同源末端连接 (NHEJ) 和作为备用的替代 NHEJ 是细胞处理 DSB 的主要途径。因此，它们的功能代表了肿瘤细胞抗辐射的主要机制。 HRR 还需要克服复制压力——复制压力是导致基因组不稳定性的一个重要因素，从而促进癌症的发展。 HRR 和替代 NHEJ 显示出强烈的细胞周期依赖性，并且可能受益于放射治疗介导的肿瘤细胞在整个细胞周期中的重新分布。此外，HRR 缺乏和 PARP 抑制之间记录的合成致死表型为靶向治疗开辟了新途径。这些观察结果使 HRR 成为旨在提高放射治疗疗效的治疗中特别有趣的目标。在这里，我们简要描述 DSB 修复的主要途径，并回顾它们对癌细胞放射抗性的可能贡献。最后，我们讨论了针对 DSB 修复的有前景的替代方案，以改善放射治疗和癌症治疗。
Radiation therapy plays an important role in the management of a wide range of cancers. Besides innovations in the physical application of radiation dose, radiation therapy is likely to benefit from novel approaches exploiting differences in radiation response between normal and tumor cells. While ionizing radiation induces a variety of DNA lesions, including base damages and single-strand breaks, the DNA double-strand break (DSB) is widely considered as the lesion responsible not only for the aimed cell killing of tumor cells, but also for the general genomic instability that leads to the development of secondary cancers among normal cells. Homologous recombination repair (HRR), non-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, are the major pathways utilized by cells for the processing of DSBs. Therefore, their function represents a major mechanism of radiation resistance in tumor cells. HRR is also required to overcome replication stress – a potent contributor to genomic instability that fuels cancer development. HRR and alternative NHEJ show strong cell-cycle dependency and are likely to benefit from radiation therapy mediated redistribution of tumor cells throughout the cell-cycle. Moreover, the synthetic lethality phenotype documented between HRR deficiency and PARP inhibition has opened new avenues for targeted therapies. These observations make HRR a particularly intriguing target for treatments aiming to improve the efficacy of radiation therapy. Here, we briefly describe the major pathways of DSB repair and review their possible contribution to cancer cell radioresistance. Finally, we discuss promising alternatives for targeting DSB repair to improve radiation therapy and cancer treatment.