Jekimovs Christian, Bolderson Emma, Suraweera Amila, Adams Mark, O'Byrne Kenneth J, Richard Derek J
Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology , Brisbane, QLD , Australia.
Front Oncol. 2014 Apr 22;4:86. doi: 10.3389/fonc.2014.00086. eCollection 2014.
The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell's genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.
DNA双链断裂（DSB）的修复是一种关键的细胞机制，其存在的目的是确保基因组稳定性。DNA DSB是对细胞遗传物质最具危害性的损伤类型，可导致基因组不稳定、细胞凋亡或衰老。修复错误的DNA DSB有可能产生染色体易位和基因组不稳定，进而可能导致癌症。由于生长失控和修复错误，DNA DSB在癌症中普遍存在，这为癌症治疗开辟了一个潜在的治疗窗口。细胞对DNA DSB的反应由两条途径组成，以确保DNA断裂得到修复：同源重组和非同源末端连接。鉴定针对这些DNA修复途径中相关蛋白的化疗化合物，已显示出有望成为一种癌症治疗方法，无论是作为单一疗法还是与基因毒性药物联合使用。从一开始，就有许多化疗化合物在临床上取得了成功的疗效，有一些失败了（如CGK - 733和依尼帕利），同时也确定了一些未来研究中很有前景的靶点。这篇综述详细探讨了细胞如何对这些DNA DSB做出反应，并研究了过去和目前正在探索的针对这一修复过程的化疗途径。
