Lyons, Gary, Tao, Haiyan, Miraglia, Loren, Orth, Anthony, Wu, Xu, Schultz, Peter and Stolz, Barbara (0020) GNF ID 100607: Identification of RNF4 as a Modulator of DNA Demethylation through Functional Genomics Screen. Nature Cell Biology.

Abstract

DNA methylation is an important epigenetic modification involved in
transcriptional regulation, nuclear organization, organism development, aging
and disease1. Although DNA methyltransferases have been characterized, the
mechanisms for reversible methylation regulation remain poorly understood2-4.
Using a cell-based reporter assay, we performed a functional genomics screen to
identify genes involved in DNA demethylation. Here we show that RNF4 (RING
finger protein 4), a SUMO-dependent ubiquitin E3-ligase previously implicated
in maintaining genome stability5,6, plays key roles in active DNA demethylation.
RNF4 re-activates methylation-silenced reporters and promotes global DNA
demethylation. We observed that Rnf4-deficiency is embryonic lethal with higher
levels of methylation in genomic DNA. Mechanistic analysis demonstrated that
RNF4 interacts with and requires the base excision repair (BER) enzymes TDG
and APE1 for active demethylation. This activity appears to occur by stimulating
the enzymatic activities that repair DNA G:T mismatches generated from
methyl-cytosine deamination. Collectively, our study unveiled novel functions of
RNF4, which may serve as a direct link between epigenetic DNA demethylation
and DNA repair in mammalian cells.

Item Type:	Article
Additional Information:	Novel genomics screen has revealed RNF4 as a modulator of DNA active demethylation through base excision repair (BER). This is the publication request following our previous request on 02/06/09, which has been approved to submit. The original manuscript has been revised according to reviewers comments, and additional experiments and new figures are added. We show that RNF4 is involved in active demethylation by enhancing BER pathway activity.
Date Deposited:	13 Oct 2015 13:16
Last Modified:	13 Oct 2015 13:16
URI:	https://oak.novartis.com/id/eprint/3117