Cyclin A overexpression induces chromosomal double-strand breaks in mammalian cells.
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.
Tane
Shoji
S
Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo, Japan.
Chibazakura
Taku
T
D000818:Animals; D019925:Cyclin A / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D016196:S Phase
D019925:Cyclin A; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; C468783:H2AX protein, human; C475961:gamma-H2AX protein, mouse