Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents
Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents
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DOI：
10.18632/oncotarget.17254
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发表时间：
2017-06-20
期刊：
影响因子：
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通讯作者：
Berdis, Anthony
中科院分区：
文献类型：
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作者：
Choi, Jung-Suk;Kim, Seol;Berdis, Anthony
抗癌药物通过破坏DNA发挥治疗作用。不幸的是，DNA聚合酶可以有效地复制形成的DNA损伤，导致耐药性和更具侵袭性的癌症。为了在细胞水平上了解这一过程，我们开发了一种人造核苷，它可以可视化受损DNA的复制，以识别通过这一机制获得耐药性的细胞。在与受损的DNA相反掺入核苷类似物后，使用化学方法将含叠氮的荧光团共价连接到核苷类似物上的乙炔基团上，从而实现可视化。流式细胞术和显微镜技术表明，DNA损伤剂处理后，核苷酸掺入基因组DNA的程度得到了增强。此外，这种核苷类似物抑制跨病变DNA合成，并协同某些抗癌药物的治疗活性，如替莫唑胺。这种人工合成的核苷类似物的综合诊断和治疗活动代表了个性化医学的新范式。
Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using "click" chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced by treatment with DNA damaging agents. In addition, this nucleoside analog inhibits translesion DNA synthesis and synergizes the therapeutic activity of certain anticancer agents such as temozolomide. The combined diagnostic and therapeutic activities of this synthetic nucleoside analog represent a new paradigm in personalized medicine.