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Critical role for mouse Hus1 in an S-phase DNA damage cell cycle checkpoint.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2003 Feb; Vol. 23 (3), pp. 791-803. - Publication Year :
- 2003
-
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.
- Subjects :
- 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide toxicity
Animals
Cell Cycle Proteins genetics
Cells, Cultured
Checkpoint Kinase 1
G2 Phase genetics
G2 Phase physiology
Gene Targeting
Mice
Mice, Knockout
Mitosis genetics
Mitosis physiology
Phosphorylation
Protein Kinases metabolism
S Phase drug effects
S Phase genetics
S Phase radiation effects
Schizosaccharomyces cytology
Schizosaccharomyces genetics
Schizosaccharomyces pombe Proteins
Ultraviolet Rays adverse effects
Cell Cycle Proteins physiology
DNA Damage
S Phase physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 23
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 12529385
- Full Text :
- https://doi.org/10.1128/MCB.23.3.791-803.2003