Cancer Cell：胸苷激酶(TMPK)抑制剂或可治疗肿瘤

7月10日，Cancer Cell杂志报道，肿瘤细胞需要胸苷激酶来阻止在DNA修复时dUTP的掺入。研究者还发现一种胸苷激酶的有效抑制剂，为研究新的治疗方法打下了基础。

脱氧胸苷二磷酸（dTDP）的合成是独特的，因为这需要胸苷激酶（TMPK）的参与。包括脱氧尿苷二磷酸（dUDP）在内的所有其他二磷酸脱氧核糖核苷（dNDPs），均由核糖核酸还原酶（RNR）直接催化产生。

本研究发现TMPK和RNR可结合在 DNA损伤位点上。在肿瘤细胞中，当TMPK功能被阻断，dUTP即被掺入DNA双链断裂（DSB）修复中。阻断RNR招募到破坏位点或减少RNR的 R2亚基的表达，可防止由TMPK阻断所导致的DNA修复障碍。这表明，RNR可促进dUTP掺入DSB修复。

本研究确定了一个无毒的，细胞渗透性的TMPK抑制剂：YMU1，它可使肿瘤细胞在体外和体内试验中，均对阿霉素敏感，提示其可能作为一种新的治疗选项。

doi:10.1016/j.cell.2011.10.017
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Tumor Cells Require Thymidylate Kinase to Prevent dUTP Incorporation during DNA Repair

Chun-Mei Hu1,Ming-Tyng Yeh4,Ning Tsao5,Chih-Wei Chen1,Quan-Ze Gao2,Chia-Yun Chang1,Ming-Hsiang Lee5,Jim-Min Fang4,Sheh-Yi Sheu2, 3,Chow-Jaw Lin1,Mei-Chun Tseng6,Yu-Ju Chen6,Zee-Fen Chang1

The synthesis of dTDP is unique because there is a requirement for thymidylate kinase (TMPK). All other dNDPs including dUDP are directly produced by ribonucleotide reductase (RNR). We report the binding of TMPK and RNR at sites of DNA damage. In tumor cells, when TMPK function is blocked, dUTP is incorporated during DNA double-strand break (DSB) repair. Disrupting RNR recruitment to damage sites or reducing the expression of the R2 subunit of RNR prevents the impairment of DNA repair by TMPK intervention, indicating that RNR contributes to dUTP incorporation during DSB repair. We identified a cell-permeable nontoxic inhibitor of TMPK that sensitizes tumor cells to doxorubicin in vitro and in vivo, suggesting its potential as a therapeutic option.