HAUSP Is a Key Epigenetic Regulator of the Chromatin Effector Proteins

HAUSP (herpes virus-associated ubiquitin-specific protease), also known as Ubiquitin Specific Protease 7, plays critical roles in cellular processes, such as chromatin biology and epigenetics, through the regulation of different signaling pathways. HAUSP is a main partner of the “Epigenetic Code Replication Machinery,” ECREM, a large protein complex that includes several epigenetic players, such as the ubiquitin-like containing plant homeodomain (PHD) and an interesting new gene (RING), finger domains 1 (UHRF1), as well as DNA methyltransferase 1 (DNMT1), histone deacetylase 1 (HDAC1), histone methyltransferase G9a, and histone acetyltransferase TIP60. Due to its deubiquitinase activity and its ability to team up through direct interactions with several epigenetic regulators, mainly UHRF1, DNMT1, TIP60, the histone lysine methyltransferase EZH2, and the lysine-specific histone demethylase LSD1, HAUSP positions itself at the top of the regulatory hierarchies involved in epigenetic silencing of tumor suppressor genes in cancer. This review highlights the increasing role of HAUSP as an epigenetic master regulator that governs a set of epigenetic players involved in both the maintenance of DNA methylation and histone post-translational modifications.

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

Genes ◽

10.3390/genes12050622 ◽

2021 ◽

Vol 12 (5) ◽

pp. 622

Author(s):

Omeima Abdullah ◽

Ziad Omran ◽

Salman Hosawi ◽

Ali Hamiche ◽

Christian Bronner ◽

...

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

Ring Finger ◽

Macromolecular Complex ◽

Anticancer Activities ◽

Histone Deacetylase 1 ◽

Promoter Dna Methylation ◽

New Gene ◽

Regulatory Effects ◽

Promoter Dna

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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Ubiquitin-specific Protease 11 (USP11) Deubiquitinates Hybrid Small Ubiquitin-like Modifier (SUMO)-Ubiquitin Chains to Counteract RING Finger Protein 4 (RNF4)

Journal of Biological Chemistry ◽

10.1074/jbc.m114.618132 ◽

2015 ◽

Vol 290 (25) ◽

pp. 15526-15537 ◽

Cited By ~ 19

Author(s):

Ivo A. Hendriks ◽

Joost Schimmel ◽

Karolin Eifler ◽

Jesper V. Olsen ◽

Alfred C. O. Vertegaal

Keyword(s):

Ring Finger ◽

Ring Finger Protein ◽

Finger Protein ◽

Specific Protease ◽

Ubiquitin Specific Protease

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Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways

Technology in Cancer Research & Treatment ◽

10.1177/1533033820947489 ◽

2020 ◽

Vol 19 ◽

pp. 153303382094748

Author(s):

Mahmoud Alhosin ◽

Syed Shoeb I. Razvi ◽

Ryan A. Sheikh ◽

Jalaluddin A. Khan ◽

Mazin A. Zamzami ◽

...

Keyword(s):

Cell Viability ◽

Dna Methyltransferase ◽

Synergistic Effects ◽

Lymphoblastic Leukemia ◽

Ring Finger ◽

Jurkat Cells ◽

Irreversible Inhibitor ◽

Cytotoxic Effects ◽

Histone Deacetylase 1 ◽

Underlying Mechanisms

Thymoquinone (TQ), a natural anticancer agent exerts cytotoxic effects on several tumors by targeting multiple pathways, including apoptosis. Difluoromethylornithine (DFMO), an irreversible inhibitor of the ornithine decarboxylase (ODC) enzyme, has shown promising inhibitory activities in many cancers including leukemia by decreasing the biosynthesis of the intracellular polyamines. The present study aimed to investigate the combinatorial cytotoxic effects of TQ and DFMO on human acute T lymphoblastic leukemia Jurkat cells and to determine the underlying mechanisms. Here, we show that the combination of DFMO and TQ significantly reduced cell viability and resulted in significant synergistic effects on apoptosis when compared to either DFMO or TQ alone. RNA-sequencing showed that many key epigenetic players including Ubiquitin-like containing PHD and Ring finger 1 (UHRF1) and its 2 partners DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) were down-regulated in DFMO-treated Jurkat cells. The combination of DFMO and TQ dramatically decreased the expression of UHRF1, DNMT1 and HDAC1 genes compared to either DFMO or TQ alone. UHRF1 knockdown led to a decrease in Jurkat cell viability. In conclusion, these results suggest that the combination of DFMO and TQ could be a promising new strategy for the treatment of human acute T lymphoblastic leukemia by targeting the epigenetic code.

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Deubiquitinase ubiquitin‐specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells

Cancer Science ◽

10.1111/cas.13953 ◽

2019 ◽

Vol 110 (4) ◽

pp. 1268-1278 ◽

Cited By ~ 5

Author(s):

Qin Lu ◽

Dayun Lu ◽

Zhi‐Ming Shao ◽

Da‐Qiang Li

Keyword(s):

Ubiquitin Ligase ◽

Breast Cancer Cells ◽

E3 Ubiquitin Ligase ◽

Ring Finger ◽

Ring Finger Protein ◽

Finger Protein ◽

Specific Protease ◽

Ubiquitin Specific Protease ◽

The Stability ◽

And Function

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Reciprocal Activities between Herpes Simplex Virus Type 1 Regulatory Protein ICP0, a Ubiquitin E3 Ligase, and Ubiquitin-Specific Protease USP7

Journal of Virology ◽

10.1128/jvi.79.19.12342-12354.2005 ◽

2005 ◽

Vol 79 (19) ◽

pp. 12342-12354 ◽

Cited By ~ 94

Author(s):

Chris Boutell ◽

Mary Canning ◽

Anne Orr ◽

Roger D. Everett

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Regulatory Protein ◽

Ring Finger ◽

Specific Protease ◽

Ubiquitin Specific Protease ◽

Protein Icp0 ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 stimulates lytic infection and the reactivation of quiescent viral genomes. These roles of ICP0 require its RING finger E3 ubiquitin ligase domain, which induces the degradation of several cellular proteins, including components of promyelocytic leukemia nuclear bodies and centromeres. ICP0 also interacts very strongly with the cellular ubiquitin-specific protease USP7 (also known as HAUSP). We have shown previously that ICP0 induces its own ubiquitination and degradation in a RING finger-dependent manner, and that its interaction with USP7 regulates this process. In the course of these studies we found and report here that ICP0 also targets USP7 for ubiquitination and proteasome-dependent degradation. The reciprocal activities of the two proteins reveal an intriguing situation that poses the question of the balance of the two processes during productive HSV-1 infection. Based on a thorough analysis of the properties of an HSV-1 mutant virus that expresses forms of ICP0 that are unable to bind to USP7, we conclude that USP7-mediated stabilization of ICP0 is dominant over ICP0-induced degradation of USP7 during productive HSV-1 infection. We propose that the biological significance of the ICP0-USP7 interaction may be most pronounced in natural infection situations, in which limited amounts of ICP0 are expressed.

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TIP60 governs the auto-ubiquitination of UHRF1 through USP7 dissociation from the UHRF1/USP7 complex

10.21203/rs.3.rs-66228/v1 ◽

2020 ◽

Author(s):

Tanveer Ahmad ◽

Waseem Ashraf ◽

Abdulkhaleg Ibrahim ◽

Liliyana Zaayter ◽

Christian D. Muller ◽

...

Keyword(s):

Dna Methyltransferase ◽

Ring Finger ◽

Fluorescence Lifetime Imaging ◽

Cellular Functions ◽

Apoptotic Pathway ◽

Cellular Processes ◽

Lifetime Imaging ◽

Damage Repair ◽

Microscopy Techniques

Abstract Background: The epigenetic regulator UHRF1 (Ubiquitin-like, containing PHD and RING finger domains 1) plays an essential role in faithful transmission of DNA methylation during replication. It has tumorogenesis potential and is overexpressed in cancers. TIP60 (Tat interactive protein, 60 kDa) is an important partner of UHRF1, ensuring various cellular processes through its acetyltransferase activity. TIP60 is believed to exert a tumor suppressive role partly explained by its down-regulation in many cancers. Both proteins participate in various cellular functions such as chromatin remodeling, cell cycle, DNA damage repair and regulation of protein stability.Methods: Immunoprecipitation and confocal microscopy techniques were performed to study the ubiquitination of UHRF1 and USP-UHRF1 association. Fluorescence lifetime imaging microscopy (FLIM) technique was performed to analyze the interaction between UHRF1 and ubiquitin inside the nucleus. Western blotting was used to assess the effect of TIP60 overexpression on p73, pro- and anti-apoptotic proteins. TIP60-mediated apoptosis in HeLa cells was investigated by flow cytometry. Results were statistically analyzed using Graphpad prism.Results: Herein, our goal was to investigate the role and mechanism of TIP60 in the regulation of UHRF1 expression. Our results showed that TIP60 overexpression down-regulated UHRF1 and DNMT1 (DNA methyltransferase 1) expressions. TIP60 interfered with USP7-UHRF1 association and induced degradation of UHRF1 in an auto-ubiquitination dependent pathway. Moreover, TIP60 activated the p73-mediated apoptotic pathway.Conclusion: Taken together, our data suggest that the tumor suppressor role of TIP60 is mediated by its regulation to UHRF1.

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Faculty Opinions recommendation of A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1020208.230491 ◽

2004 ◽

Author(s):

Paul J Lehner

Keyword(s):

Ubiquitin Ligase ◽

Ring Finger ◽

Specific Protease ◽

Ubiquitin Specific Protease

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Gfi1 Coordinates Epigenetic Repression of p21Cip/WAF1 by Recruitment of Histone Lysine Methyltransferase G9a and Histone Deacetylase 1

Molecular and Cellular Biology ◽

10.1128/mcb.25.23.10338-10351.2005 ◽

2005 ◽

Vol 25 (23) ◽

pp. 10338-10351 ◽

Cited By ~ 118

Author(s):

Zhijun Duan ◽

Adrian Zarebski ◽

Diego Montoya-Durango ◽

H. Leighton Grimes ◽

Marshall Horwitz

Keyword(s):

Cell Fate ◽

Histone Deacetylase ◽

Histone H3 ◽

Hematopoietic Stem ◽

Histone Deacetylase 1 ◽

Histone Lysine ◽

Histone Lysine Methyltransferase ◽

Lysine Methyltransferase ◽

Cell Processes ◽

Epigenetic Repression

ABSTRACT The growth factor independent 1 (Gfi1) transcriptional regulator oncoprotein plays a crucial role in hematopoietic, inner ear, and pulmonary neuroendocrine cell development and governs cell processes as diverse as self-renewal of hematopoietic stem cells, proliferation, apoptosis, differentiation, cell fate specification, and oncogenesis. However, the molecular basis of its transcriptional functions has remained elusive. Here we show that Gfi1 recruits the histone lysine methyltransferase G9a and the histone deacetylase 1 (HDAC1) in order to modify the chromatin of genes targeted for repression by Gfi1. G9a and HDAC1 are both in a repressive complex assembled by Gfi1. Endogenous Gfi1 colocalizes with G9a, HDAC1, and K9-dimethylated histone H3. Gfi1 associates with G9a and HDAC1 on the promoter of the cell cycle regulator p21 Cip/WAF1 , resulting in an increase in K9 dimethylation at histone H3. Silencing of Gfi1 expression in myeloid cells reverses G9a and HDAC1 recruitment to p21 Cip/WAF1 and elevates its expression. These findings highlight the role of epigenetics in the regulation of development and oncogenesis by Gfi1.

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