SMK-1/PPH-4.1-mediated silencing of the CHK-1 response to DNA damage in early C. elegans embryos.
During early embryogenesis in Caenorhabditis elegans, the ATL-1-CHK-1 (ataxia telangiectasia mutated and Rad3 related-Chk1) checkpoint controls the timing of cell division in the future germ line, or P lineage, of the animal. Activation of the CHK-1 pathway by its canonical stimulus DNA damage is actively suppressed in early embryos so that P lineage cell divisions may occur on schedule. We recently found that the rad-2 mutation alleviates this checkpoint silent DNA damage response and, by doing so, causes damage-dependent delays in early embryonic cell cycle progression and subsequent lethality. In this study, we report that mutations in the smk-1 gene cause the rad-2 phenotype. SMK-1 is a regulatory subunit of the PPH-4.1 (protein phosphatase 4) protein phosphatase, and we show that SMK-1 recruits PPH-4.1 to replicating chromatin, where it silences the CHK-1 response to DNA damage. These results identify the SMK-1-PPH-4.1 complex as a critical regulator of the CHK-1 pathway in a developmentally relevant context.
Kim
Seung-Hwan
SH
The Biological Laboratories, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Holway
Antonia H
AH
Wolff
Suzanne
S
Dillin
Andrew
A
Michael
W Matthew
WM
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000201:enzymology / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004625:Embryo, Nonmammalian / Q000201:enzymology; D047108:Embryonic Development / Q000235:genetics; D004789:Enzyme Activation; D008136:Longevity / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D002843:Chromatin; D021122:Protein Subunits; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605876:chk-1 protein, C elegans; D010749:Phosphoprotein Phosphatases; C525403:SMK-1 protein, C elegans; C080406:protein phosphatase 4