Biochemical and dynamic basis for combinatorial recognition of H3R2K9me2 by dual domains of UHRF1

Abhishek, Suman; Nivya, M Angel; Nakarakanti, Naveen Kumar; Deeksha, Waghela; Khosla, Sanjeev; Rajakumara, Eerappa

doi:10.1016/j.biochi.2018.04.010

Cited by 5 publications

(3 citation statements)

References 49 publications

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“…However, the PHD fingers of these proteins are accompanied by other domains, in a tandem fashion, that bind to the extended tail of histone peptides. For example, the TTD domain in UHRF1 recognizes H3K9me2/3 , and the bromodomains of BAZ2A and BAZ2B recognize acetylated lysine marks in histones H3 and H4 . In VIM1, no such domain has yet been reported.…”

Section: Discussionmentioning

confidence: 99%

Helical and β-Turn Conformations in the Peptide Recognition Regions of the VIM1 PHD Finger Abrogate H3K4 Peptide Recognition

2021

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The PHD finger-containing VARIANT IN METHYLATION/ORTHRUS (VIM/ORTH) family of proteins in Arabidopsis consists of functional homologues of mammalian UHRF1 and is required for the maintenance of DNA methylation. Comparison of the sequence with those of other PHD fingers implied that VIM1 and VIM3 PHD could recognize lysine 4 of histone H3 (H3K4) through interactions mediated by a conserved aspartic acid. However, our calorimetric and modified histone peptide array binding studies suggested that neither H3K4 nor other histone marks are recognized by VIM1 and VIM3 PHD fingers. Here, we report a 2.6 Å resolution crystal structure of the VIM1 PHD finger and demonstrate significant structural changes in the putative H3 recognition segments in contrast to canonical H3K4 binding PHD fingers. These changes include (i) the H3A1 binding region, (ii) strand β1 that forms an intermolecular β-sheet with the H3 peptide, and (iii) an aspartate-containing motif involved in salt bridge interaction with H3K4, which together appear to abrogate recognition of H3K4 by the VIM1 PHD finger. To understand the significance of the altered structural features in the VIM1 PHD that might prevent histone H3 recognition, we modeled a chimeric VIM1 PHD (chmVIM1 PHD) by grafting the peptide binding structural features of the BHC80 PHD onto the VIM1 PHD. Molecular dynamics simulation and metadynamics analyses revealed that the chmVIM1 PHD-H3 complex is stable and also showed a network of intermolecular interactions similar to those of the BHC80 PHD-H3 complex. Collectively, this study reveals that subtle structural changes in the peptide binding region of the VIM1 PHD abrogate histone H3 recognition.

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Section: Discussionmentioning

confidence: 99%

Helical and β-Turn Conformations in the Peptide Recognition Regions of the VIM1 PHD Finger Abrogate H3K4 Peptide Recognition

2021

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“…The UHRF1BP1 gene encodes a putative‐binding protein of UHRF1 (also known as ICBP90), a RING‐finger‐type E3 ubiquitin ligase that recruits a histone deacetylase to regulate gene expression (Abhishek et al., ). This protein is highly conserved through evolution and widely expressed in multiple tissues according to RNA‐seq expression data from GTEx.…”

Section: Discussionmentioning

confidence: 99%

The association of the UHRF1BP1 gene with systemic lupus erythematosus was replicated in a Han Chinese population from mainland China

Wen

Liu

Shen

et al. 2019

Annals of Human Genetics

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Single‐nucleotide polymorphisms (SNPs) in the UHRF gene have been shown to be associated with systemic lupus erythematosus (SLE) in European and Hong Kong Chinese, but statistically significant evidence for association has not been found in a mainland Han Chinese population. Therefore, we selected SNP rs13205210 located in UHRF1BP1 as a candidate association from our previously published genome‐wide association study (GWAS) data of SLE (1,047 cases and 1,205 controls from a mainland Han Chinese population) to explore the association between the UHRF1BP1 gene and SLE. We conducted a large‐scale replication study in an additional independent sample of 3,509 cases and 8,246 controls from a mainland Han Chinese population. Real‐time PCR was used to determine gene expression differences in peripheral blood mononuclear cells (PBMCs) from cases and controls. As a result, we replicated the association between the UHRF1BP1 gene and SLE (rs13205210, missense, Pmeta = 2.26E‐17, odds ratio = 1.41) by a meta‐analysis of our previous GWAS and this replication study involving a total of 4,556 cases and 9,451 controls. The UHRF1BP1 mRNA expression level in PBMCs was significantly decreased in patients with SLE compared with that in healthy controls. SNP rs13205210 exhibited an expression quantitative trait loci effect on the UHRF1BP1 gene in PBMCs from patients. In conclusion, this study not only suggests that the UHRF1BP1 gene was associated with SLE in a mainland Han Chinese population, but also implied that it might be a common genetic factor contributing to SLE susceptibility in multiple populations.

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“…These enzymes work in coordination with another group of epigenetic players, called readers, which are proteins containing specialized domains that can identify and interpret an epigenetic mark in the chromatin structure and can recruit the right writer or eraser to its correct position [ 4 ]. One intriguing epigenetic reader is a ubiquitin-like containing plant homeodomain (PHD) and an interesting new gene (RING) finger domains 1 (UHRF1), which can act as a sensor of both types of epigenetic marks (DNA methylation and histone marks) and recruit the corresponding writers, DNA methyltransferase 1 (DNMT1) and G9A, or eraser histone deacetylase 1 (HDAC1), to the right place to catalyze the same epigenetic mark [ 5 , 6 , 7 , 8 , 9 , 10 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Thymoquinone Is a Multitarget Single Epidrug That Inhibits the UHRF1 Protein Complex

Abdullah

Omran

Hosawi

et al. 2021

Genes

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Silencing of tumor suppressor genes (TSGs) through epigenetic mechanisms, mainly via abnormal promoter DNA methylation, is considered a main mechanism of tumorigenesis. The abnormal DNA methylation profiles are transmitted from the cancer mother cell to the daughter cells through the involvement of a macromolecular complex in which the ubiquitin-like containing plant homeodomain (PHD), and an interesting new gene (RING) finger domains 1 (UHRF1), play the role of conductor. Indeed, UHRF1 interacts with epigenetic writers, such as DNA methyltransferase 1 (DNMT1), histone methyltransferase G9a, erasers like histone deacetylase 1 (HDAC1), and functions as a hub protein. Thus, targeting UHRF1 and/or its partners is a promising strategy for epigenetic cancer therapy. The natural compound thymoquinone (TQ) exhibits anticancer activities by targeting several cellular signaling pathways, including those involving UHRF1. In this review, we highlight TQ as a potential multitarget single epidrug that functions by targeting the UHRF1/DNMT1/HDAC1/G9a complex. We also speculate on the possibility that TQ might specifically target UHRF1, with subsequent regulatory effects on other partners.

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Biochemical and dynamic basis for combinatorial recognition of H3R2K9me2 by dual domains of UHRF1

Cited by 5 publications

References 49 publications

Helical and β-Turn Conformations in the Peptide Recognition Regions of the VIM1 PHD Finger Abrogate H3K4 Peptide Recognition

Helical and β-Turn Conformations in the Peptide Recognition Regions of the VIM1 PHD Finger Abrogate H3K4 Peptide Recognition

The association of the UHRF1BP1 gene with systemic lupus erythematosus was replicated in a Han Chinese population from mainland China

Thymoquinone Is a Multitarget Single Epidrug That Inhibits the UHRF1 Protein Complex

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