title: A novel regulatory circuit in base excision repair involving AP endonuclease 1, Creb1 and DNA polymerase beta.
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.
authors.affiliation: Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: De-Sheng
authors.initials: DS
authors.lastname: Pei
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Jeroen E J
authors.initials: JE
authors.lastname: Guikema
authors.forename: Carol E
authors.initials: CE
authors.lastname: Schrader
authors.forename: Phyllis R
authors.initials: PR
authors.lastname: Strauss
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016159:Tumor Suppressor Protein p53; D019951:DNA Polymerase beta; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase