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. Cells lacking mouse Hus1 are hypersensitive to certain genotoxins, 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.
Weiss
Robert S
RS
Department of Genetics, Boston, MA 02115, USA.
Matsuoka
Shuhei
S
Elledge
Stephen J
SJ
Leder
Philip
P
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000528:radiation effects; D011494:Protein Kinases / Q000378:metabolism*; D011839:Radiation, Ionizing; D029702:Schizosaccharomyces pombe Proteins; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014466:Ultraviolet Rays / Q000009:adverse effects
D018797:Cell Cycle Proteins; D029702:Schizosaccharomyces pombe Proteins; D016159:Tumor Suppressor Protein p53; C106332:hus1 protein, S pombe; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605873:Chk1 protein, S pombe