Abstract
Chk1 is a conserved kinase that imposes cell cycle delays in response to impediments to DNA replication. Recent experiments have further defined effects of Chk1 on the activity of mammalian origins of DNA replication and progression of replication forks. Moreover, Chk1 now appears to help defend genomic integrity through effects on several other pathways, including Fanconi anemia proteins, the mitotic spindle, and transcription of cell cycle-related genes. These findings can account for the requirement for Chk1 in normal proliferating cells of the early embryo and suggest the potential for diverse effects of Chk1 inhibition in cancer therapy.
Highlights
The most precious possession for any organism is its genetic dowry
Chk1 heterozygous mammary epithelia display evidence of early mitotic entry, prior to completion of DNA synthesis, accompanied by increased DNA damage [11]. These and other data have firmly established a role for Chk1 in restraining mitotic entry in response to DNA damage and replication blocks, in part by inhibiting cyclin-dependent kinase (Cdk) activity
Experiments revealed that Chk1 stabilizes replication forks and inhibits firing of origins of DNA replication that are normally activated in late S phase [13, 14]
Summary
The most precious possession for any organism is its genetic dowry. Eukaryotic cells store their genomic inheritance in DNA, partitioned into discrete chromosomes. These and other data have firmly established a role for Chk1 in restraining mitotic entry in response to DNA damage and replication blocks, in part by inhibiting Cdk activity. DNA damage that occurs during DNA replication normally activates a checkpoint that delays cells within S phase, mediated in part by Chk1 and Chk2 [7, 12].
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