Expanded roles for Chk1 in genome maintenance

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.

FIGURE 1.

Multiple roles for Chk1 in genome maintenance. Chk1 is activated by DNA damage and other impediments to DNA replication (through ATR). Chk1 inhibits firing of origins of DNA replication (Ori), progression of replication forks, and activity of Cdks. Chk1 contributes to function of centrosomeand spindle-based checkpoints, activation of FA proteins, and repression of transcription of cell cycle proteins such as cyclin B and Cdk1. The base-line permissive (positive) role for Chk1 at cell cycle gene promoters has been omitted for simplicity. Note that the depicted functions may overlap. In particular, inhibition of Cdks and transcriptional repression may mediate some of the effects of Chk1 on other pathways.