Chronic myeloid leukemia (CML) is characterized by the formation of the BCR-ABL fusion gene. The BCR-ABL protein leads to an increased level of reactive oxygen species, which is a major cause of endogenous DNA double-strand breaks (DSBs). CML cells are prone to rely on a highly mutagenic alternative end-joining (Alt-EJ) pathway to cope with enhanced DSBs, which aggravates chromosomal instability. Hence, targeting dysregulated DNA repair proteins provides new insights into cancer treatment. In this study, we discovered the abnormal upregulation of Flap endonuclease 1 (FEN1) in CML, as well as FEN1's participation in the error-prone Alt-EJ repair pathway and its interplay with DNA Ligase1 and proliferating cell nuclear antigen in DSB repair. Knockdown of FEN1 by shRNA not only inhibited the proliferation and induced apoptosis but also enhanced the efficacy of imatinib (IM) in drug-resistant CML cell K562/G01. Moreover, excessive DSB accumulation was detected after FEN1 inhibition. In summary, our results demonstrated that FEN1 is a promising therapeutic target in CML treatment. This work extends the understanding of regulating abnormal DSB repair for cancer treatment.

中文翻译：

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靶向 FEN1 通过调节替代端连接通路抑制慢性粒细胞白血病细胞的增殖

慢性粒细胞白血病 (CML) 的特征是BCR-ABL的形成融合基因。BCR-ABL 蛋白导致活性氧水平增加，这是内源性 DNA 双链断裂 (DSB) 的主要原因。CML 细胞倾向于依靠高度诱变的替代末端连接 (Alt-EJ) 途径来应对增强的 DSB，这会加剧染色体的不稳定性。因此，靶向失调的 DNA 修复蛋白为癌症治疗提供了新的见解。在这项研究中，我们发现了 CML 中 Flap 核酸内切酶 1 (FEN1) 的异常上调，以及 FEN1 参与容易出错的 Alt-EJ 修复途径及其在 DSB 修复中与 DNA Ligase1 和增殖细胞核抗原的相互作用。shRNA 对 FEN1 的敲低不仅抑制增殖并诱导细胞凋亡，而且还增强了伊马替尼 (IM) 在耐药 CML 细胞 K562/G01 中的疗效。而且，在 FEN1 抑制后检测到过度的 DSB 积累。总之，我们的结果表明 FEN1 是 CML 治疗中一个有前景的治疗靶点。这项工作扩展了对调节异常 DSB 修复以用于癌症治疗的理解。