Hemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition

Fang, Jian; Cheng, Jingdong; Wang, Jiaolong; Zhang, Qiao; Liu, Mengjie; Gong, Rui; Wang, Ping; Zhang, Xiaodan; Feng, Yangyang; Lan, Wenxian; Gong, Zhou; Tang, Chun; Wong, Jiemin; Yang, Huirong; Cao, Chunyang; Xu, Yanhui

doi:10.1038/ncomms11197

Cited by 112 publications

(133 citation statements)

References 56 publications

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“…Uhrf1 contains multiple domains (Figure S7F), which recognize or set up specific chromatin marks (Bostick et al, 2007; Liu et al, 2013; Nishiyama et al, 2013; Qin et al, 2015; Rothbart et al, 2013; Sharif et al, 2007) and are also involved in intra-molecular interactions critical for Uhrf1 conformation (Fang et al, 2016). Mutagenesis and co-IP experiments indicated that deletion of the TTD (tandem tudor domain), PHD (plant homeodomain) or RING (Really Interesting New Gene) domain abolished the interaction between Uhrf1 and Zscan4c, whereas deletion of the UBL (ubiquitin-like) or SRA (SET and RING associated) domain had no effect (Figure S7F).…”

Section: Resultsmentioning

confidence: 99%

Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

et al. 2017

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SUMMARY Proper telomere length is essential for embryonic stem cell (ESC) self-renewal and pluripotency. Mouse ESCs (mESCs) sporadically convert to a transient totipotent state similar to that of two-cell (2C) embryos to recover shortened telomeres. Zscan4, which exhibits a burst of expression in 2C-like mESCs, is required for telomere extension in these cells. However, the mechanism by which Zscan4 extends telomeres remains elusive. Here, we show that Zscan4 facilitates telomere elongation by inducing global DNA demethylation through downregulation of Uhrf1 and Dnmt1, major components of the maintenance DNA methylation machinery. Mechanistically, Zscan4 recruits Uhrf1 and Dnmt1 and promotes their degradation that is dependent on the E3 ubiquitin ligase activity of Uhrf1. Importantly, blocking DNA demethylation prevents telomere elongation associated with Zscan4 expression, suggesting that DNA demethylation mediates the effect of Zscan4. Our results define a molecular pathway that contributes to the maintenance of telomere length homeostasis in mESCs.

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Section: Resultsmentioning

confidence: 99%

Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

et al. 2017

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“…29 This was also supported by crystallographic studies on TTD-PHD bound to H3K9me3 which showed that UHRF1 possesses the ability to get engaged with both unmodified N terminus of H3 and H3K9me3 simultaneously. 30 SRA domain occurs only in UHRF family and helps in recognition of hemi-methylated DNA as well as recruitment of DNA (cytosine-5)-methyltransferase 1 (DNMT1) for ensuring faithful methylation. 31 The DNA interaction mediated by the crescent moon-shaped SRA domain could be explained by representation of a hand grasping the DNA helix with a conserved methyl cytosine binding pocket situated in the palm.…”

Section: Uhrf1: the Facilitator Between Dna Methylation And Histone Mmentioning

confidence: 99%

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

Sidhu

Capalash

2017

Tumour Biol.

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UHRF1 is a master regulator of epigenome as it coordinates DNA methylation and histone modifications. Compelling evidence suggests a strong link between UHRF1 overexpression and tumorigenesis, substantiating its ability to act as a potential biomarker for cancer diagnosis and prognosis. UHRF1 also mediates repair of damaged DNA that makes cancer cells resistant toward cytocidal drugs. Hence, understanding the molecular mechanism of UHRF1 regulation would help in developing cancer therapeutics. Natural compounds have shown applicability to downregulate UHRF1 leading to growth arrest and apoptosis in cancer cells.

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“…Alternatively, through the E3 ligase activity of its RING domain, UHRF1, can also mediate the ubiquitylation of H3K23 and H3K18, creating binding sites for DNMT1 . The presence of hemi‐methylated CpG sites plays a primary role in driving UHRF1 conformational changes, which consequently allow the SRA domain to flip the mC residues facilitating the recruitment of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

A Molecular Tool Targeting the Base‐Flipping Activity of Human UHRF1

Zaayter

Mori

Ahmad

et al. 2019

Chemistry A European J

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During DNA replication, ubiquitin‐like, containing PHD and RING fingers domains 1 (UHRF1) plays key roles in the inheritance of methylation patterns to daughter strands by recognizing through its SET and RING‐associated domain (SRA) the methylated CpGs and recruiting DNA methyltransferase 1 (DNMT1). Herein, our goal is to identify UHRF1 inhibitors targeting the 5′‐methylcytosine (5mC) binding pocket of the SRA domain to prevent the recognition and flipping of 5mC and determine the molecular and cellular consequences of this inhibition. For this, we used a multidisciplinary strategy combining virtual screening and molecular modeling with biophysical assays in solution and cells. We identified an anthraquinone compound able to bind to the 5mC binding pocket and inhibit the base‐flipping process in the low micromolar range. We also showed in cells that this hit impaired the UHRF1/DNMT1 interaction and decreased the overall methylation of DNA, highlighting the critical role of base flipping for DNMT1 recruitment and providing the first proof of concept of the druggability of the 5mC binding pocket. The selected anthraquinone appears thus as a key tool to investigate the role of UHRF1 in the inheritance of methylation patterns, as well as a starting point for hit‐to‐lead optimizations.

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Hemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition

Cited by 112 publications

References 56 publications

Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

A Molecular Tool Targeting the Base‐Flipping Activity of Human UHRF1

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