Hus1 Acts Upstream of Chk1 in a Mammalian DNA Damage Response Pathway

The evolutionarily conserved Hus1 proteins function in DNA damage response pathways that serve to maintain genomic stability [1, 2]. Cells lacking mouse Hus1 are hypersensitive to certain genotoxins [3], and we have explored the molecular basis for this defect by examining how Hus1 inactivation affects genotoxin-induced signaling events. p53 accumulation and activation in response to DNA damage appeared normal in Hus1 null cells. Likewise, Hus1 was dispensable for genotoxin-induced Chk2 phosphorylation. In contrast, Chk1 phosphorylation after genotoxic stress was greatly reduced in the absence of Hus1, but was restored in Hus1 null fibroblasts complemented by infection with a Hus1 -expressing retrovirus. These results demonstrate that mouse Hus1 is required for a specific subset of DNA damage signaling events and functions to promote genotoxin-induced Chk1 phosphorylation.