title: Critical role for mouse Hus1 in an S-phase DNA damage cell cycle checkpoint.
abstract: Mouse Hus1 encodes an evolutionarily conserved DNA damage response protein. In this study we examined how targeted deletion of Hus1 affects cell cycle checkpoint responses to genotoxic stress. Unlike hus1(-) fission yeast (Schizosaccharomyces pombe) cells, which are defective for the G(2)/M DNA damage checkpoint, Hus1-null mouse cells did not inappropriately enter mitosis following genotoxin treatment. However, Hus1-deficient cells displayed a striking S-phase DNA damage checkpoint defect. Whereas wild-type cells transiently repressed DNA replication in response to benzo(a)pyrene dihydrodiol epoxide (BPDE), a genotoxin that causes bulky DNA adducts, Hus1-null cells maintained relatively high levels of DNA synthesis following treatment with this agent. However, when treated with DNA strand break-inducing agents such as ionizing radiation (IR), Hus1-deficient cells showed intact S-phase checkpoint responses. Conversely, checkpoint-mediated inhibition of DNA synthesis in response to BPDE did not require NBS1, a component of the IR-responsive S-phase checkpoint pathway. Taken together, these results demonstrate that Hus1 is required specifically for one of two separable mammalian checkpoint pathways that respond to distinct forms of genome damage during S phase.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.forename: Philip
authors.initials: P
authors.lastname: Leder
authors.forename: Cyrus
authors.initials: C
authors.lastname: Vaziri
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D016195:G2 Phase / Q000235:genetics / Q000502:physiology; D018390:Gene Targeting; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D012568:Schizosaccharomyces / Q000166:cytology / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D018797:Cell Cycle Proteins; D029702:Schizosaccharomyces pombe Proteins; C106332:hus1 protein, S pombe; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1