PUBLICATION

Mutation of the zebrafish nucleoporin elys sensitizes tissue progenitors to replication stress

Authors
Davuluri, G., Gong, W., Yusuff, S., Lorent, K., Muthumani, M., Dolan, A.C., and Pack, M.
ID
ZDB-PUB-081105-5
Date
2008
Source
PLoS Genetics   4(10): e1000240 (Journal)
Registered Authors
Dolan, Amy, Lorent, Kristin, Pack, Michael
Keywords
Larvae, Gastrointestinal tract, DNA replication, Apoptosis, Zebrafish, Chromatin, Morpholino, Embryos
MeSH Terms
  • Animals
  • Cell Cycle
  • DNA Replication*
  • Retina/cytology
  • Retina/embryology
  • Retina/metabolism
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Amino Acid Sequence
  • DNA Damage
  • Nuclear Pore Complex Proteins/chemistry
  • Nuclear Pore Complex Proteins/genetics*
  • Nuclear Pore Complex Proteins/physiology*
  • Protein Serine-Threonine Kinases/metabolism
  • Molecular Sequence Data
  • Zebrafish/genetics*
  • Zebrafish/growth & development
  • Zebrafish/physiology
  • Genes, p53
  • Apoptosis*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/physiology*
  • Intestines/cytology
  • Intestines/embryology
  • Intestines/metabolism
  • Mutation*
  • Transcription Factors/metabolism
  • Checkpoint Kinase 2
(all 29)
PubMed
18974873 Full text @ PLoS Genet.
Abstract
The recessive lethal mutation flotte lotte (flo) disrupts development of the zebrafish digestive system and other tissues. We show that flo encodes the ortholog of Mel-28/Elys, a highly conserved gene that has been shown to be required for nuclear integrity in worms and nuclear pore complex (NPC) assembly in amphibian and mammalian cells. Maternal elys expression sustains zebrafish flo mutants to larval stages when cells in proliferative tissues that lack nuclear pores undergo cell cycle arrest and apoptosis. p53 mutation rescues apoptosis in the flo retina and optic tectum, but not in the intestine, where the checkpoint kinase Chk2 is activated. Chk2 inhibition and replication stress induced by DNA synthesis inhibitors were lethal to flo larvae. By contrast, flo mutants were not sensitized to agents that cause DNA double strand breaks, thus showing that loss of Elys disrupts responses to selected replication inhibitors. Elys binds Mcm2-7 complexes derived from Xenopus egg extracts. Mutation of elys reduced chromatin binding of Mcm2, but not binding of Mcm3 or Mcm4 in the flo intestine. These in vivo data indicate a role for Elys in Mcm2-chromatin interactions. Furthermore, they support a recently proposed model in which replication origins licensed by excess Mcm2-7 are required for the survival of human cells exposed to replication stress.
Genes / Markers
Figures
Figure Gallery (11 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
m74
    Point Mutation
    ti262c
      Point Mutation
      zdf1
        Point Mutation
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        ahctf1MO1-ahctf1MRPHLNO
        ahctf1MO2-ahctf1MRPHLNO
        ahctf1MO3-ahctf1MRPHLNO
        tp53MO3-tp53MRPHLNO
        tp53MO4-tp53MRPHLNO
        1 - 5 of 5
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        Fish
        Antibodies
        Name Type Antigen Genes Isotypes Host Organism
        Ab1-mcm2polyclonalIgG1Rabbit
        Ab1-mcm3polyclonalIgGRabbit
        Ab1-mcm4polyclonalRabbit
        Ab1-nucleoporinmonoclonal
          IgG1Mouse
          Ab1-rhomonoclonalMouse
          Ab2-chek1polyclonal
            Rabbit
            Ab2-chek2polyclonal
              Rabbit
              Ab-2F11monoclonalIgG1Mouse
              Ab2-h2afxpolyclonalRabbit
              Ab3-chek2polyclonalRabbit
              1 - 10 of 12
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              Orthology
              No data available
              Engineered Foreign Genes
              No data available
              Mapping
              Entity Type Entity Symbol Location
              Featureti262cChr: 17 Details
              SSLPz24006Chr: 17 Details
              SSLPz24082Chr: 17 Details
              SSLPz54789Chr: 17 Details
              1 - 4 of 4
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