7月10日,，Cancer Cell雜志報道,，腫瘤細胞需要胸苷激酶來阻止在DNA修復時dUTP的摻入。研究者還發(fā)現(xiàn)一種胸苷激酶的有效抑制劑,，為研究新的治療方法打下了基礎,。
脫氧胸苷二磷酸（dTDP）的合成是獨特的，因為這需要胸苷激酶（TMPK）的參與,。包括脫氧尿苷二磷酸（dUDP）在內的所有其他二磷酸脫氧核糖核苷（dNDPs）,，均由核糖核酸還原酶（RNR）直接催化產生。
本研究發(fā)現(xiàn)TMPK和RNR可結合在 DNA損傷位點上。在腫瘤細胞中,，當TMPK功能被阻斷,，dUTP即被摻入DNA雙鏈斷裂（DSB）修復中。阻斷RNR招募到破壞位點或減少RNR的 R2亞基的表達,，可防止由TMPK阻斷所導致的DNA修復障礙,。這表明,，RNR可促進dUTP摻入DSB修復,。
本研究確定了一個無毒的，細胞滲透性的TMPK抑制劑：YMU1,，它可使腫瘤細胞在體外和體內試驗中,，均對阿霉素敏感，提示其可能作為一種新的治療選項,。（生物谷bioon.com）
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.
