Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo, Japan.
Cell Cycle. 2009 Dec;8(23):3900-3. doi: 10.4161/cc.8.23.10071. Epub 2009 Dec 14.
Cyclin A is a major regulator in vertebrate cell cycle, associated with cyclin-dependent kinase (Cdk), and involved in S-phase progression and entry into mitosis. It has been known that cyclin A overexpression not only causes premature S-phase entry but also induces prolongation of S phase. Here we show that ectopic expression of cyclin A leads to extensive gamma-H2AX focus formation, which is indicative of DNA double-strand breaks. Likewise, cyclin E, but not cyclin B1 and cyclin D1, also induced the gamma-H2AX focus formation, suggesting that these DNA lesions may be induced via aberrant DNA replication process. Moreover, the gamma-H2AX focus formation was suppressed by co-expressing p21(Cip1/Waf1) or dominant-negative Cdk2 mutant, suggesting that aberrant cyclin A-Cdk2 activation induces the chromosomal double-strand breaks.
细胞周期蛋白 A 是脊椎动物细胞周期的主要调节因子，与细胞周期蛋白依赖性激酶（Cdk）相关，参与 S 期进展和进入有丝分裂。已知细胞周期蛋白 A 的过度表达不仅导致过早的 S 期进入，还导致 S 期延长。在这里，我们表明细胞周期蛋白 A 的异位表达导致广泛的 γ-H2AX 焦点形成，这表明存在 DNA 双链断裂。同样，细胞周期蛋白 E，但不是细胞周期蛋白 B1 和细胞周期蛋白 D1，也诱导了 γ-H2AX 焦点形成，表明这些 DNA 损伤可能是通过异常的 DNA 复制过程诱导的。此外，γ-H2AX 焦点形成被共表达 p21（Cip1/Waf1）或显性失活 Cdk2 突变体所抑制，表明异常的细胞周期蛋白 A-Cdk2 激活诱导染色体双链断裂。
