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Structural insights by molecular dynamics simulations into specificity of the major human AP endonuclease toward the benzene-derived DNA adduct, pBQ-C

Nucleic Acids Research
Oxford University Press
Publication Date
DOI: 10.1093/nar/gkh594
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OP-NARE131261 1..13 PGC7 suppresses TET3 for protecting DNA methylation Chunjing Bian and Xiaochun Yu* Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, 1150 W. Medical Center Drive, 5560 MSRBII, Ann Arbor, MI 48109, USA Received June 27, 2013; Revised November 11, 2013; Accepted November 12, 2013 ABSTRACT Ten-eleven translocation (TET) family enzymes con- vert 5-methylcytosine to 5-hydroxylmethylcytosine. However, the molecular mechanism that regulates this biological process is not clear. Here, we show the evidence that PGC7 (also known as Dppa3 or Stella) interacts with TET2 and TET3 both in vitro and in vivo to suppress the enzymatic activity of TET2 and TET3. Moreover, lacking PGC7 induces the loss of DNA methylation at imprinting loci. Genome- wide analysis of PGC7 reveals a consensusDNAmotif that is recognized by PGC7. The CpG islands surrounding the PGC7-binding motifs are hypermethylated. Taken together, our study demon- strates a molecular mechanism by which PGC7 protects DNA methylation from TET family enzyme- dependent oxidation. INTRODUCTION DNA methylation at the 5 position of the cytosine pyr- imidine ring (5mC) in genomic DNA is an important epi- genetic mark that regulates gene transcription during numerous physiological and pathological processes (1–5). In particular, during early embryogenesis, DNA methylation is dynamically regulated to precisely control transcription for defining cell fate (6–8). A global DNA demethylation occurs in the paternal pronucleus of a zygote, which is likely to remove epigenetic barriers that restrict gene transcription and developmental potential (9–11). This active DNA demethylation process is mediated by TET family enzymes that oxidize methyl groups at the 5 position of cytosine pyrimidine rings into hydroxymethyl groups (5hmC) in the presence of 2-oxoglutarate (2-OG) and Fe(II) (11–13). Further oxida- tion, probably catalyzed by these oxygenases, generates 5-formylc

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