{
  "id": 10017085,
  "title": "A feed-forward UHRF1 read-write mechanism supports H3 multi- mono-ubiquitination and DNA methylation maintenance at CpG-sparse regions",
  "url": "https://urgent.news/2026/09/26/a-feed-forward-uhrf1-read-write-mechanism-supports-h3-multi-mono",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-26T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754493v1?rss=1"
  },
  "original_language": "en",
  "account": "At newly replicated mammalian chromatin, the epigenetic inheritance of DNA methylation relies on DNMT1 and its E3 ligase cofactor UHRF1. UHRF1 identifies hemi-methylated DNA and histone H3 N-terminal tails to catalyze mono-ubiquitination of H3K14, H3K18, and/or H3K23, recruiting DNMT1 for methylation maintenance. While UHRF1 can deposit multiple mono-ubiquitin marks on a single H3 tail and DNMT1 recognizes this state through tandem ubiquitin interacting motifs, the mechanism behind successive ubiquitination and the significance of multi-mono-ubiquitination were unclear. This study reveals that UHRF1 directly binds its mono-ubiquitinated H3 products via a unique LGDDSL loop in Tudor 2 of its tandem Tudor domain (TTD), facilitating further ubiquitin deposition.\n\nWhen this ubiquitin reading activity is disrupted, it hampers H3 multi-mono-ubiquitination and accelerates DNA methylation loss in late-replicating, CpG-sparse genomic regions, which are typical of partially methylated domains (PMDs) observed in cancer and aging cells. These methylation defects align with those seen in UHRF1 ubiquitin ligase activity disruption, suggesting that both writing and reading of H3 ubiquitination contribute to maintaining CpG-sparse DNA methylation. The findings establish a feed-forward ubiquitin read-write mechanism that generates multi-mono-ubiquitinated H3 and preserves DNMT1-dependent DNA methylation at vulnerable genomic regions of the mammalian methylome.",
  "summary": "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…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}