Abstract
In most cells, the DNA damage checkpoint delays cell division when replication is stalled by DNA damage. In early Caenorhabditis elegans embryos, however, the checkpoint responds to developmental signals that control the timing of cell division, and checkpoint activation by nondevelopmental inputs disrupts cell cycle timing and causes embryonic lethality. Given this sensitivity to inappropriate checkpoint activation, we were interested in how embryos respond to DNA damage. We demonstrate that the checkpoint response to DNA damage is actively silenced in embryos but not in the germ line. Silencing requires rad-2, gei-17, and the polh-1 translesion DNA polymerase, which suppress replication fork stalling and thereby eliminate the checkpoint-activating signal. These results explain how checkpoint activation is restricted to developmental signals during embryogenesis and insulated from DNA damage. They also show that checkpoint activation is not an obligatory response to DNA damage and that pathways exist to bypass the checkpoint when survival depends on uninterrupted progression through the cell cycle.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Caenorhabditis elegans / embryology*
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Caenorhabditis elegans Proteins / physiology
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Cell Cycle / drug effects
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Cell Cycle / radiation effects
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cell Division / drug effects
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Cell Division / radiation effects
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Checkpoint Kinase 1
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Cytochalasin B / pharmacology
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DNA Damage*
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DNA Repair
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DNA Replication / genetics
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DNA-Directed DNA Polymerase / genetics
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Down-Regulation
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Embryo, Nonmammalian / drug effects
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Embryo, Nonmammalian / embryology*
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Embryo, Nonmammalian / radiation effects
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Endodeoxyribonucleases / genetics
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Genes, cdc / physiology
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Germ Cells / drug effects
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Germ Cells / metabolism
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Germ Cells / radiation effects
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Hydroxyurea / pharmacology
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Ligases / genetics
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Methyl Methanesulfonate / pharmacology
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Mitosis / drug effects
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Mitosis / radiation effects
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Models, Biological
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Mutation
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Phosphotransferases / genetics
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Protein Kinases / genetics
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RNA, Small Interfering / genetics
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Rad51 Recombinase / genetics
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Rad51 Recombinase / metabolism
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Recombinases / genetics
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Ubiquitin-Conjugating Enzymes / genetics
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Ultraviolet Rays
Substances
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Caenorhabditis elegans Proteins
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Cell Cycle Proteins
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RNA, Small Interfering
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Recombinases
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Cytochalasin B
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Methyl Methanesulfonate
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Ubiquitin-Conjugating Enzymes
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ubc-1 protein, C elegans
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Atl-1 protein, C elegans
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Phosphotransferases
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Protein Kinases
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Ataxia Telangiectasia Mutated Proteins
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Checkpoint Kinase 1
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Rad51 Recombinase
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rad-51 protein, C elegans
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DNA-Directed DNA Polymerase
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Rad30 protein
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Endodeoxyribonucleases
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Ligases
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Hydroxyurea