Simultaneous Targeting of DNA Polymerase Theta and PARP1 or RAD52 Triggers Dual Synthetic Lethality in Homologous Recombination-Deficient Leukemia Cells.
Simultaneous Targeting of DNA Polymerase Theta and PARP1 or RAD52 Triggers Dual Synthetic Lethality in Homologous Recombination-Deficient Leukemia Cells.
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DOI：
10.1158/1541-7786.mcr-22-1035
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发表时间：
2023-10-02
影响因子：
5.2
通讯作者：
Skorski, Tomasz
中科院分区：
文献类型：
--
作者：
Sullivan-Reed, Katherine;Toma, Monika M.;Drzewiecka, Malgorzata;Nieborowska-Skorska, Margaret;Nejati, Reza;Karami, Adam;Wasik, Mariusz A.;Sliwinski, Tomasz;Skorski, Tomasz
DNA聚合酶θ（Polymerase theta，POLQ）在DNA双链断裂（DSB）的末端连接（end-joining，TMEJ）过程中起重要作用。抑制Polθ在同源重组（HR）缺陷型肿瘤细胞中是合成致死性的。然而，DSB也可以通过PARP 1和RAD 52介导的机制修复。由于白血病细胞积累自发DSB，我们测试了同时靶向Polθ和PARP 1或RAD 52是否增强HR缺陷型白血病细胞中的合成致死效应。与单一敲除相比，在Polq−/−; Parp 1 −/−和Polq−/−; Rad 52 −/−细胞中，诱导BRCA 1/2缺陷的癌基因（BCR-ABL 1和AML 1-ETO）的转化潜力受到严重限制，这与DSB的积累有关。Polθ的小分子抑制剂（Polθi）与PARP或RAD 52抑制剂（PARPi、RAD 52 i）联合使用时，可引起DSB蓄积，并对HR缺陷型白血病和骨髓增生性肿瘤细胞产生更强的作用。总之，我们表明PARPi或RAD 52 i可能提高Polθi对HR缺陷型白血病的治疗效果。
DNA polymerase theta (Polθ, encoded by POLQ gene) plays an essential role in Polθ-mediated end-joining (TMEJ) of DNA double-strand breaks (DSB). Inhibition of Polθ is synthetic lethal in homologous recombination (HR)-deficient tumor cells. However, DSBs can be also repaired by PARP1 and RAD52-mediated mechanisms. Because leukemia cells accumulate spontaneous DSBs, we tested if simultaneous targeting of Polθ and PARP1 or RAD52 enhance the synthetic lethal effect in HR-deficient leukemia cells. Transformation potential of the oncogenes inducing BRCA1/2-deficiency (BCR-ABL1 and AML1-ETO) was severely limited in Polq−/−;Parp1−/− and Polq−/−;Rad52−/− cells when compared with single knockouts, which was associated with accumulation of DSBs. Small-molecule inhibitor of Polθ (Polθi) when combined with PARP or RAD52 inhibitors (PARPi, RAD52i) caused accumulation of DSBs and exerted increased effect against HR-deficient leukemia and myeloproliferative neoplasm cells. In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polθi against HR-deficient leukemias.