A Study of "UHRF2 commissions the completion of DNA demethylation through allosteric activation by 5hmC and K33-linked ubiquitination of XRCC1", Liu et al
The transition of oxidized 5-methylcytosine (5mC) intermediates into the base excision repair (BER) pipeline to complete DNA demethylation remains enigmatic. We report here that UHRF2, the only paralogue of UHRF1 in mammals that is neither able to maintain 5mC nor to rescue Uhrf1-/- phenotype, is physically and functionally associated with BER. We show that UHRF2 is allosterically activated by 5-hydroxymethylcytosine (5hmC) and acts as a ubiquitin E3 ligase to catalyze K33-linked polyubiquitination of XRCC1, a core subunit of the BER complex. This nonproteolytic action stimulates the interaction of XRCC1 with the ubiquitin binding domain-bearing RAD23B, leading to the incorporation of TDG into the BER complex. Integrative epigenomic analysis in mouse embryonic stem cells reveals that the Uhrf2-commissioned TDG-RAD23B-BER complex functionally links to the completion of DNA demethylation at active promoters, and that during neuronal commitment, Uhrf2-associated and H3K4me1-marked latent enhancers undergo poised-to-active transition, accompanied by complete DNA demethylation and H3K27ac acquisition. Accordingly, Uhrf2 ablation impedes DNA demethylation and inhibits neuronal differentiation. Together, these observations highlight an essentiality of 5hmC-switched UHRF2 E3 ligase activity in commissioning the accomplishment of active DNA demethylation. Raw data for " UHRF2 commissions the completion of DNA demethylation through allosteric activation by 5hmC and K33-linked ubiquitination of XRCC1" is presented here.