Checking in on Cds1 (Chk2): A checkpoint kinase and tumor suppressor

Abstract

Together, DNA repair and checkpoint responses ensure the integrity of the genome. Coordination of cell cycle checkpoints and DNA repair are especially important following genotoxic radiation or chemotherapy, during which unusually high loads of DNA damage are sustained. In mammalian cells, the checkpoint kinase, Cds1 (also known as Chk2) is activated by ATM in response to DNA damage. The role of Cds1 as a checkpoint kinase depends on its ability to phosphorylate cell cycle regulators such p53, Cdc25 and Brca1. A role for Cds1 in repair is suggested by the finding that it interacts with the Holliday junction resolving activity Mus81. This review focuses on the many questions generated by recent progress in understanding the function and regulation of human Cds1.

Chk2 is required for optimal mitotic delay in response to irradiation-induced DNA damage incurred in G2 phase

“…In contrast, when cells were treated with the DNA polymerase inhibitor aphidicolin little, if any, activation of Chk2 was detected (Figure 2, lower panel). Taken together, these results are consistent with observations in other cell types (McGowan, 2002) and indicate that in DT40 cells Chk2 is activated strongly in response to DNA damage but weakly if at all by DNA synthesis inhibition. Furthermore, the finding that Chk2 is rapidly and quantitatively activated after irradiation of an asynchronous culture (at least at 4 Gy) implies that activation in response to DNA damage occurs in all phases of the cell cycle.…”

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

“…In mammalian cells, these multiple CDKs and cyclins which regulate passage through the cell cycle can be classified to four main groups by the stage of cell cycle: McGowan, 2002 Fig. 1.4).…”

BRCA1 gene in breast cancer

“…DNA damage activated nuclear kinases (e.g., ATM, ATR, chk1, chk2) promote survival, in part, by activating specific DNA damage-responsive cell cycle checkpoints, including those in G1/S, intra-S, and G2/M (reviewed in McGowan, 2002;Melo and Toczyski, 2002). These checkpoints play an important protective function by preventing the propagation of DNA damage by cell cycle progression occurring before the DNA is repaired.…”