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Cyclin A-Cdk1 regulates the origin firing program in mammalian cells.


ABSTRACT: Somatic mammalian cells possess well-established S-phase programs with specific regions of the genome replicated at precise times. The ATR-Chk1 pathway plays a central role in these programs, but the mechanism for how Chk1 regulates origin firing remains unknown. We demonstrate here the essential role of cyclin A2-Cdk1 in the regulation of late origin firing. Activity of cyclin A2-Cdk1 was hardly detected at the onset of S phase, but it was obvious at middle to late S phase under unperturbed condition. Chk1 depletion resulted in increased expression of Cdc25A, subsequent hyperactivation of cyclin A2-Cdk1, and abnormal replication at early S phase. Hence, the ectopic expression of cyclin A2-Cdk1AF (constitutively active mutant) fusion constructs resulted in abnormal origin firing, causing the premature appearance of DNA replication at late origins at early S phase. Intriguingly, inactivation of Cdk1 in temperature-sensitive Cdk1 mutant cell lines (FT210) resulted in a prolonged S phase and inefficient activation of late origin firing even at late S phase. Our results thus suggest that cyclin A2-Cdk1 is a key regulator of S-phase programs.

SUBMITTER: Katsuno Y 

PROVIDER: S-EPMC2651338 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Cyclin A-Cdk1 regulates the origin firing program in mammalian cells.

Katsuno Yuko Y   Suzuki Ayumi A   Sugimura Kazuto K   Okumura Katsuzumi K   Zineldeen Doaa H DH   Shimada Midori M   Niida Hiroyuki H   Mizuno Takeshi T   Hanaoka Fumio F   Nakanishi Makoto M  

Proceedings of the National Academy of Sciences of the United States of America 20090212 9


Somatic mammalian cells possess well-established S-phase programs with specific regions of the genome replicated at precise times. The ATR-Chk1 pathway plays a central role in these programs, but the mechanism for how Chk1 regulates origin firing remains unknown. We demonstrate here the essential role of cyclin A2-Cdk1 in the regulation of late origin firing. Activity of cyclin A2-Cdk1 was hardly detected at the onset of S phase, but it was obvious at middle to late S phase under unperturbed con  ...[more]

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