PUBLICATION

DNA hypomethylation activates Cdk4/6 and Atr to induce DNA replication and cell cycle arrest to constrain liver outgrowth in zebrafish

Authors
Madakashira, B.P., Magnani, E., Ranjan, S., Sadler, K.C.
ID
ZDB-PUB-240207-8
Date
2024
Source
Nucleic acids research   52(6): 3069-3087 (Journal)
Registered Authors
Magnani, Elena, Ranjan, Shashi, Sadler Edepli, Kirsten C.
Keywords
none
Datasets
GEO:GSE234993
MeSH Terms
  • Animals
  • Ataxia Telangiectasia Mutated Proteins*/genetics
  • Ataxia Telangiectasia Mutated Proteins*/metabolism
  • Cell Cycle/genetics
  • Cell Cycle Checkpoints/genetics
  • Cell Division/genetics
  • Cyclin-Dependent Kinase 4*/genetics
  • Cyclin-Dependent Kinase 4*/metabolism
  • Cyclin-Dependent Kinase 6*/genetics
  • Cyclin-Dependent Kinase 6*/metabolism
  • DNA/metabolism
  • DNA Methylation*
  • DNA Replication/genetics
  • Embryo, Nonmammalian
  • Enzyme Activation/genetics
  • Liver*/growth & development
  • Liver*/metabolism
  • S Phase
  • Zebrafish*/genetics
  • Zebrafish*/metabolism
(all 20)
PubMed
38321933 Full text @ Nucleic Acids Res.
Abstract
Coordinating epigenomic inheritance and cell cycle progression is essential for organogenesis. UHRF1 connects these functions during development by facilitating maintenance of DNA methylation and cell cycle progression. Here, we provide evidence resolving the paradoxical phenotype of uhrf1 mutant zebrafish embryos which have activation of pro-proliferative genes and increased number of hepatocytes in S-phase, but the liver fails to grow. We uncover decreased Cdkn2a/b and persistent Cdk4/6 activation as the mechanism driving uhrf1 mutant hepatocytes into S-phase. This induces replication stress, DNA damage and Atr activation. Palbociclib treatment of uhrf1 mutants prevented aberrant S-phase entry, reduced DNA damage, and rescued most cellular and developmental phenotypes, but it did not rescue DNA hypomethylation, transposon expression or the interferon response. Inhibiting Atr reduced DNA replication and increased liver size in uhrf1 mutants, suggesting that Atr activation leads to dormant origin firing and prevents hepatocyte proliferation. Cdkn2a/b was downregulated pro-proliferative genes were also induced in a Cdk4/6 dependent fashion in the liver of dnmt1 mutants, suggesting DNA hypomethylation as a mechanism of Cdk4/6 activation during development. This shows that the developmental defects caused by DNA hypomethylation are attributed to persistent Cdk4/6 activation, DNA replication stress, dormant origin firing and cell cycle inhibition.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
c269TgTransgenic Insertion
    hi272TgTransgenic Insertion
    mss4TgTransgenic Insertion
      mss8TgTransgenic Insertion
        nya1TgTransgenic Insertion
          s904
            		Point Mutation
            zf3425TgTransgenic Insertion
              1 - 7 of 7
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              Human Disease / Model
              Sequence Targeting Reagents
              Target Reagent Reagent Type
              dnmt1CRISPR4-dnmt1CRISPR
              dnmt1CRISPR5-dnmt1CRISPR
              dnmt1CRISPR6-dnmt1CRISPR
              dnmt1CRISPR7-dnmt1CRISPR
              slc45a2CRISPR1-slc45a2CRISPR
              1 - 5 of 5
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              Fish
              No data available
              Antibodies
              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              EGFPEFGEGFP
              GAL4EFGGAL4
              mCherryEFGmCherry
              1 - 3 of 3
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              Mapping
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              Citation
              Madakashira, B.P., Magnani, E., Ranjan, S., Sadler, K.C. (2024) DNA hypomethylation activates Cdk4/6 and Atr to induce DNA replication and cell cycle arrest to constrain liver outgrowth in zebrafish. Nucleic acids research. 52(6):3069-3087.