Graduate Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 11221 Taiwan.
Cancer Cell. 2012 Jul 10;22(1):36-50. doi: 10.1016/j.ccr.2012.04.038.
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.
dTDP 的合成是独特的，因为它需要胸苷酸激酶 (TMPK)。所有其他 dNDPs，包括 dUDP，都是直接由核糖核苷酸还原酶 (RNR) 产生的。我们报告了 TMPK 和 RNR 在 DNA 损伤部位的结合。在肿瘤细胞中，当 TMPK 功能被阻断时，dUTP 会在 DNA 双链断裂 (DSB) 修复过程中被掺入。破坏 RNR 对损伤部位的募集或降低 RNR 的 R2 亚基的表达，可以防止 TMPK 干预对 DNA 修复的损害，表明 RNR 有助于 DSB 修复过程中 dUTP 的掺入。我们鉴定了一种细胞通透性的 TMPK 非毒性抑制剂，它可以增加肿瘤细胞对阿霉素的敏感性，这表明它有作为一种治疗选择的潜力。
