Checkpoint silencing during the DNA damage response in Caenorhabditis elegans embryos.
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.
Holway
Antonia H
AH
The Biological Laboratories, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Kim
Seung-Hwan
SH
La Volpe
Adriana
A
Michael
W Matthew
WM
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D003571:Cytochalasin B / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D015536:Down-Regulation; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000196:embryology* / Q000528:radiation effects; D004706:Endodeoxyribonucleases / Q000235:genetics; D018816:Genes, cdc / Q000502:physiology; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006918:Hydroxyurea / Q000494:pharmacology; D008025:Ligases / Q000235:genetics; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D008954:Models, Biological; D009154:Mutation; D010770:Phosphotransferases / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D045522:Recombinases / Q000235:genetics; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
D064007:Ataxia Telangiectasia Mutated Proteins; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D003571:Cytochalasin B; D004259:DNA-Directed DNA Polymerase; D004706:Endodeoxyribonucleases; D006918:Hydroxyurea; D008025:Ligases; D008741:Methyl Methanesulfonate; D010770:Phosphotransferases; D011494:Protein Kinases; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase; D045522:Recombinases; D044763:Ubiquitin-Conjugating Enzymes; C489359:ubc-1 protein, C elegans; C576885:Atl-1 protein, C elegans; C495148:rad-51 protein, C elegans; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases