Futami Kazunobu, Kumagai Emi, Makino Hiroshi, Goto Hideyuki, Takagi Motoki, Shimamoto Akira, Furuichi Yasuhiro
GeneCare Research Institute, 19-2 Kajiwara, Kamakura, Kanagawa 247-0063, Japan.
Cancer Sci. 2008 Jan;99(1):71-80. doi: 10.1111/j.1349-7006.2007.00647.x. Epub 2007 Oct 22.
RecQL1 DNA helicase of the human RecQ helicase family participates in DNA repair and recombination pathways during cell-cycle replication. When we examined the effect of RecQL1 suppression on cell growth, we found that RecQL1 silencing by small interference RNA efficiently prevented proliferation of a wide range of cancer cells by inducing mitotic catastrophe and mitotic cell death. In contrast, such mitotic cell death was not seen in the growing normal fibroblasts used as controls, even if RecQL1 expression was fully downregulated. Our results support the hypothesis that endogenous DNA damage that occurs during DNA replication and remains unrepaired in cancer cells due to RecQL1 silencing induces cancer cell-specific mitotic catastrophe through a less-strict checkpoint in cancer cells than in normal cells. We speculate that normal cells are exempt from such mitotic cell death, despite slow growth, because cell-cycle progression is controlled strictly by a strong checkpoint system that detects DNA damage and arrests progression of the cell cycle until DNA damage is repaired completely. These results suggest that RecQL1 helicase is an excellent molecular target for cancer chemotherapy.
人类RecQ解旋酶家族的RecQL1 DNA解旋酶在细胞周期复制过程中参与DNA修复和重组途径。当我们研究RecQL1抑制对细胞生长的影响时，发现通过小干扰RNA使RecQL1沉默可通过诱导有丝分裂灾难和有丝分裂细胞死亡有效阻止多种癌细胞的增殖。相比之下，即使RecQL1表达完全下调，在用作对照的生长中的正常成纤维细胞中也未观察到这种有丝分裂细胞死亡。我们的结果支持这样的假说，即DNA复制过程中发生的内源性DNA损伤在癌细胞中因RecQL1沉默而未得到修复，通过癌细胞中比正常细胞更宽松的检查点诱导癌细胞特异性有丝分裂灾难。我们推测正常细胞尽管生长缓慢，但可免于这种有丝分裂细胞死亡，因为细胞周期进程由强大的检查点系统严格控制，该系统检测DNA损伤并阻止细胞周期进程，直到DNA损伤完全修复。这些结果表明RecQL1解旋酶是癌症化疗的极佳分子靶点。
