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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Pei DS,Yang XJ,Liu W,Guikema JE,Schrader CE,Strauss PR

doi

10.1093/nar/gkq1142

subject

Has Abstract

pub_date

2011-04-01 00:00:00

pages

3156-65

issue

8

eissn

0305-1048

issn

1362-4962

pii

gkq1142

journal_volume

39

pub_type

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