PUBLICATION

A novel regulatory circuit in base excision repair involving AP endonuclease 1, Creb1 and DNA polymerase beta

Authors
Pei, D.S., Yang, X.J., Liu, W., Guikema, J.E., Schrader, C.E., and Strauss, P.R.
ID
ZDB-PUB-101222-50
Date
2011
Source
Nucleic acids research   39(8): 3156-3165 (Journal)
Registered Authors
Liu, Wei, Pei, Desheng, Strauss, Phyllis, Yang, Xiaojie
Keywords
none
MeSH Terms
  • Alkylating Agents/pharmacology
  • Animals
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein/genetics
  • Cyclic AMP Response Element-Binding Protein/metabolism*
  • DNA Polymerase beta/genetics
  • DNA Polymerase beta/metabolism*
  • DNA Repair*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics
  • DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase/physiology
  • Embryo, Mammalian/drug effects
  • Embryo, Mammalian/metabolism
  • Gene Knockdown Techniques
  • Mice
  • Mice, Inbred C57BL
  • Tumor Suppressor Protein p53/metabolism
PubMed
21172930 Full text @ Nucleic Acids Res.
Abstract
DNA repair is required to maintain genome stability in stem cells and early embryos. At critical junctures, oxidative damage to DNA requires the base excision repair (BER) pathway. Since early zebrafish embryos lack the major polymerase in BER, DNA polymerase ß, repair proceeds via replicative polymerases, even though there is ample polb mRNA. Here, we report that Polb protein fails to appear at the appropriate time in development when AP endonuclease 1 (Apex), the upstream protein in BER, is knocked down. Because polb contains a Creb1 binding site, we examined whether knockdown of Apex affects creb1. Apex knockdown results in loss of Creb1 and Creb complex members but not Creb1 phosphorylation. This effect is independent of p53. Although both apex and creb1 mRNA rescue Creb1 and Polb after Apex knockdown, Apex is not a co-activator of creb1 transcription. This observation has broad significance, as similar results occur when Apex is inhibited in B cells from apex(+/-) mice. These results describe a novel regulatory circuit involving Apex, Creb1 and Polb and provide a mechanism for lethality of Apex loss in higher eukaryotes.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes