Summary
A bioRxiv preprint reports that UHRF1 reads ubiquitin marks it places on histone H3, promoting further marking and supporting DNA methylation maintenance in CpG-sparse regions.
A bioRxiv preprint posted September 26, 2026, reports a feed-forward mechanism in which UHRF1 reads ubiquitin marks it has placed on histone H3 and uses that recognition to promote further marking. The authors report that this read-write activity supports DNA methylation maintenance in late-replicating genomic regions with relatively few CpG sites.
DNA methylation is a chemical modification of DNA that cells must copy as they divide. After replication, the original DNA strand can carry methylation while the newly made strand does not yet have it. UHRF1 works with the maintenance enzyme DNMT1 at this stage, helping direct DNMT1 to newly replicated chromatin.
How UHRF1 reads the mark it writes
UHRF1 recognizes hemi-methylated DNA and the N-terminal tail of histone H3. Its E3 ligase activity adds individual ubiquitin molecules to H3 at lysine 14, 18 and/or 23. These marks help recruit DNMT1. When several such ubiquitin marks occur on one H3 tail, the state is called multi-monoubiquitination.
The preprint identifies a previously uncharacterized LGDDSL loop in Tudor 2 of UHRF1’s tandem Tudor domain as part of the reading mechanism. The authors report that UHRF1 binds its own mono-ubiquitinated H3 products through this loop. That recognition promotes additional ubiquitin deposition, creating a feedback cycle: UHRF1 writes a mark, reads it, and then helps add more.
Why the mechanism matters in CpG-sparse regions
According to the authors, disrupting UHRF1’s ubiquitin-reading activity impairs H3 multi-monoubiquitination and accelerates DNA methylation loss in late-replicating, CpG-sparse regions. These regions are characteristic of partially methylated domains, or PMDs, associated with cancer and aging cells. The reported methylation defects overlap those seen when UHRF1’s ubiquitin ligase activity is disrupted. Together, the findings point to both reading and writing histone ubiquitin marks as contributors to maintaining DNA methylation in these genomic regions.
The results are reported as a mechanistic research finding in a preprint. Its abstract describes the molecular interaction and regional methylation pattern, but does not specify the experimental models or provide quantitative effect sizes. The findings therefore identify a proposed mechanism; they do not by themselves establish a clinical implication.