UHRF1

UHRF1 Full Name

ubiquitin-like with PHD and ring finger domains 1

UHRF1 Introduction

UHRF1, also known as ICBP90 in human and NP95 in mouse, encodes a multidomain epigenetic regulator that serves as the master recruiter for the maintenance of DNA methylation. The protein contains an N-terminal ubiquitin-like domain, a plant homeodomain (PHD) finger, a really interesting new gene (RING) finger with E3 ubiquitin ligase activity, and a SET- and RING-associated (SRA) domain. These modules allow UHRF1 to integrate several molecular signals at once. Its central function is to preserve established DNA methylation patterns as cells divide: during DNA replication, the methylation marks on the parental strands must be copied onto the newly synthesized daughter strands, and UHRF1 is essential for this faithful inheritance of epigenetic information. Loss of UHRF1 disrupts this process and is linked to genome instability, reflecting how central epigenetic maintenance is to normal cell function.

Figure 1. A revised and expanded model for UHRF1 functions in DNA methylation homeostasis. (Source: Yamaguchi K, et al. 2024)

The key to UHRF1's function lies in its SRA domain, which recognizes hemimethylated CpG sites — the transient intermediates produced behind the replication fork. Structural studies show that the SRA domain captures the methylated cytosine by flipping it completely out of the DNA helix into a dedicated binding pocket, a mechanism that explains its strong preference for hemimethylated over fully methylated or unmethylated DNA. Through its direct interaction with the maintenance methyltransferase DNMT1, UHRF1 tethers DNMT1 to these sites so that the parental methylation pattern is copied onto the daughter strand. Complementary inputs come from the PHD finger, which binds histone H3 carrying the repressive mark H3K9me3, and from the RING domain, which ubiquitylates histone H3 to reinforce the chromatin state. Depletion of UHRF1 leads to widespread loss of DNA methylation, underscoring its role as the platform that couples DNA and histone signals to the methylation machinery. Because DNA methylation helps silence repetitive elements and regulate gene expression, the fidelity of this UHRF1-directed system is critical for development and tissue homeostasis.

Alternate Names for UHRF1

UHRF1; ubiquitin-like with PHD and ring finger domains 1; E3 ubiquitin-protein ligase UHRF1; FLJ21925; ICBP90; Np95; RNF106; huNp95; nuclear protein 95; RING finger protein 106

• 1. Yamaguchi K, et al. Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells. Nat Commun. 2024 Apr 5;15(1):2960.
  2. Bostick M, et al.. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science. 2007 Sep 21;317(5845):1760-4.