Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1

Abstract

The epigenetic inheritance of DNA methylation requires UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that recruits DNMT1 to sites of newly replicated DNA through ubiquitylation of histone H3. UHRF1 binds DNA with selectivity towards hemi-methylated CpGs (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. HeDNA recognition activates UHRF1 ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies are the first demonstrations of a DNA-protein interaction and an epigenetic modification directly regulating E3 ubiquitin ligase activity. They also define an orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance.DOI: http://dx.doi.org/10.7554/eLife.17101.001

EHMT1/GLP; Biochemical Function and Association with Brain Disorders

“…UHRF1 is known to co-localise and directly interact with DNMT1 and aids in the maintenance of the methylation. Through its SET/RING domain it binds preferentially to hemi-methylated DNA, recruiting DNMT1 to re-establish methylation [27,28]. UHRF1 was also shown to bind to H3K9me2/3 through its tandem Tudor domain and appears to bind DNMT1 to mediate DNA methylation maintenance in an H3K9me2/3 dependent manner [27].…”

“…Through its SET/RING domain it binds preferentially to hemi-methylated DNA, recruiting DNMT1 to re-establish methylation [27,28]. UHRF1 was also shown to bind to H3K9me2/3 through its tandem Tudor domain and appears to bind DNMT1 to mediate DNA methylation maintenance in an H3K9me2/3 dependent manner [27]. A recent paper however has increased the current understanding of this process; DNA ligase 1 (LIG1), a novel target of GLP is methylated on its H3K9 mimic, UHRF1 then binds to the mimic, and in turn this binding leads to the recruitment of UHRF1 to hemi-methylated sites, mediating its activity [29] (Figure 1).…”

The Arginine Methyltransferase PRMT6 Regulates DNA Methylation and Contributes to Global DNA Hypomethylation in Cancer

“…The SRA (SET- and RING-associated) domain of UHRF1 preferentially binds hemi-methylated DNA and plays an important role in loading DNMT1 onto newly synthesized DNA (Bostick et al, 2007, Sharif et al, 2007, Liu et al, 2013). The RING domain-mediated ubiquitination of lysine residues in the N-terminal tail of histone H3 promotes DNMT1 association with H3 (Nishiyama et al, 2013, Qin et al, 2015, Harrison et al, 2016). Moreover, the TTD (tandem Tudor domain) and PHD (plant homeodomain) cooperatively interact with the N-terminal tail of H3 by recognizing a specific histone modification signature.…”

Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

“…The SRA domain of UHRF1 behaves as a “hand” with two fingers that serve to flip out the methylated cytosine with subsequent recruitment of DNMT1 to methylate the cytosine of the newly synthetized DNA strand [9–11]. This recruitment was proposed to be under the control of SRA binding to hemi-methylated DNA, challenging enhanced activity of the UHRF1 RING finger that exhibits E3 ligase activity towards histone H3 [12, 13]. The TTD exhibits affinity for methylated histones and allows to confer a fabulous property to UHRF1 of connecting DNA methylation to histone modifications [14, 15].…”