Chk1 is haploinsufficient for multiple functions critical to tumor suppression.

The haploinsufficient tumor suppressor Chk1 is essential for embryonic cells, but the consequences of Chk1 loss in adult tissues are unknown. Using conditional Chk1 mice, we find that proliferating mammary cells lacking Chk1 undergo apoptosis leading to developmental defects. Conditional Chk1 heterozygosity increased the number of S phase cells and caused spontaneous DNA damage. Chk1+/- epithelia also exhibit a miscoordinated cell cycle in which S phase cells display an early mitotic phenotype. These cells maintain high levels of Cdc25A, which can promote inappropriate cell cycle transitions. Thus, Chk1 heterozygosity results in three distinct haploinsufficient phenotypes that can contribute to tumorigenesis: inappropriate S phase entry, accumulation of DNA damage during replication, and failure to restrain mitotic entry.