Format

Send to

Choose Destination
Differentiation. 2015 Jul-Oct;90(1-3):59-68. doi: 10.1016/j.diff.2015.10.003. Epub 2015 Nov 3.

GADD45a physically and functionally interacts with TET1.

Author information

1
Institute of Molecular Biology, 55128 Mainz, Germany.
2
Johannes Gutenberg Universität Mainz, Institut für Pharmazie und Biochemie, 55128 Mainz, Germany.
3
Institute of Molecular Biology, 55128 Mainz, Germany; DKFZ-ZMBH Alliance, Division of Molecular Embryology, 69120 Heidelberg, Germany.
4
Institute of Molecular Biology, 55128 Mainz, Germany. Electronic address: A.Schaefer@imb-mainz.de.

Abstract

DNA demethylation plays a central role during development and in adult physiology. Different mechanisms of active DNA demethylation have been established. For example, Growth Arrest and DNA Damage 45-(GADD45) and Ten-Eleven-Translocation (TET) proteins act in active DNA demethylation but their functional relationship is unresolved. Here we show that GADD45a physically interacts--and functionally cooperates with TET1 in methylcytosine (mC) processing. In reporter demethylation GADD45a requires endogenous TET1 and conversely TET1 requires GADD45a. On GADD45a target genes TET1 hyperinduces 5-hydroxymethylcytosine (hmC) in the presence of GADD45a, while 5-formyl-(fC) and 5-carboxylcytosine (caC) are reduced. Likewise, in global analysis GADD45a positively regulates TET1 mediated mC oxidation and enhances fC/caC removal. Our data suggest a dual function of GADD45a in oxidative DNA demethylation, to promote directly or indirectly TET1 activity and to enhance subsequent fC/caC removal.

KEYWORDS:

DNA demethylation; Gadd45; LC–MS/MS; TET; hmC

PMID:
26546041
PMCID:
PMC4673086
DOI:
10.1016/j.diff.2015.10.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center