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This study reveals how UHRF1, a protein essential for maintaining DNA methylation patterns during cell division, uses a feed-forward mechanism to add multiple ubiquitin marks to histone H3. The researchers discovered that UHRF1 contains a specific loop (LGDDSL) in its Tudor domain that recognizes its own ubiquitin modifications on histones, promoting additional ubiquitination that recruits DNMT1 to maintain DNA methylation. Disrupting this self-recognition mechanism impairs DNA methylation maintenance specifically in CpG-sparse genomic regions, which are areas particularly vulnerable to methylation loss in cancer and aging.
Why it matters
Understanding how DNA methylation is maintained in vulnerable genomic regions could help explain why certain areas of the genome lose methylation patterns during aging and cancer development. This mechanism may represent a potential therapeutic target for diseases characterized by aberrant DNA methylation or could inform strategies to stabilize epigenetic marks in stem cells and regenerative medicine.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
The epigenetic inheritance of mammalian DNA methylation requires DNMT1 and its E3 ligase cofactor UHRF1. At newly replicated chromatin, UHRF1 recognition of hemi-methylated DNA and histone H3 N-terminal tails directs catalysis of H3K14, H3K18, and/or H3K23 mono-ubiquitination to recruit DNMT1. While it is appreciated that UHRF1 can deposit multiple mono-ubiquitin marks on a single H3 tail and that DNMT1 recognizes this state through tandem ubiquitin interacting motifs, the mechanism that promotes successive ubiquitination and the biological function of multi-mono-ubiquitination are unknown. Here, we show that UHRF1 directly binds its mono-ubiquitinated H3 products through a previously uncharacterized LGDDSL loop in Tudor 2 of its tandem Tudor domain (TTD) to promote further ubiquitin deposition. Disruption of this ubiquitin reading activity impairs H3 multi-mono-ubiquitination and accelerates DNA methylation loss within late-replicating, CpG-sparse genomic regions that are characteristic of partially methylated domains (PMDs) in cancer and aging cells. These methylation defects overlap those observed by disruption of UHRF1 ubiquitin ligase activity, providing convergent evidence that both writing and reading of H3 ubiquitination support CpG-sparse DNA methylation maintenance. Together, these findings establish a feed-forward ubiquitin read-write mechanism that generates multi-mono-ubiquitinated H3 and safeguards DNMT1-dependent DNA methylation maintenance at vulnerable genomic regions of the mammalian methylome.