Polycomb group proteins in cancer: multifaceted functions and strategies for modulation

Abstract Polycomb repressive complexes (PRCs) are a heterogenous collection of dozens, if not hundreds, of protein complexes composed of various combinations of subunits. PRCs are transcriptional repressors important for cell-type specificity during development, and as such, are commonly mis-regulated in cancer. PRCs are broadly characterized as PRC1 with histone ubiquitin ligase activity, or PRC2 with histone methyltransferase activity; however, the mechanism by which individual PRCs, particularly the highly diverse set of PRC1s, alter gene expression has not always been clear. Here we review the current understanding of how PRCs act, both individually and together, to establish and maintain gene repression, the biochemical contribution of individual PRC subunits, the mis-regulation of PRC function in different cancers, and the current strategies for modulating PRC activity. Increased mechanistic understanding of PRC function, as well as cancer-specific roles for individual PRC subunits, will uncover better targets and strategies for cancer therapies.

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Id1 enhances RING1b E3 ubiquitin ligase activity through the Mel-18/Bmi-1 polycomb group complex

Oncogene ◽

10.1038/onc.2010.317 ◽

2010 ◽

Vol 29 (43) ◽

pp. 5818-5827 ◽

Cited By ~ 13

Author(s):

T Qian ◽

J-Y Lee ◽

J-H Park ◽

H-J Kim ◽

G Kong

Keyword(s):

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Polycomb Group ◽

Ubiquitin Ligase Activity

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Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms21228594 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8594

Author(s):

Zhuangzhuang Geng ◽

Zhonghua Gao

Keyword(s):

Molecular Mechanisms ◽

Protein Complexes ◽

Ring Finger ◽

Transcription Activation ◽

Polycomb Group ◽

Histone H2a ◽

Catalytic Core ◽

Associated Proteins ◽

Regulation Mechanisms ◽

Polycomb Repressive Complexes

Polycomb group (PcG) proteins function as vital epigenetic regulators in various biological processes, including pluripotency, development, and carcinogenesis. PcG proteins form multicomponent complexes, and two major types of protein complexes have been identified in mammals to date, Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). The PRC1 complexes are composed in a hierarchical manner in which the catalytic core, RING1A/B, exclusively interacts with one of six Polycomb group RING finger (PCGF) proteins. This association with specific PCGF proteins allows for PRC1 to be subdivided into six distinct groups, each with their own unique modes of action arising from the distinct set of associated proteins. Historically, PRC1 was considered to be a transcription repressor that deposited monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1) and compacted local chromatin. More recently, there is increasing evidence that demonstrates the transcription activation role of PRC1. Moreover, studies on the higher-order chromatin structure have revealed a new function for PRC1 in mediating long-range interactions. This provides a different perspective regarding both the transcription activation and repression characteristics of PRC1. This review summarizes new advancements regarding the composition of mammalian PRC1 and accompanying explanations of how diverse PRC1-associated proteins participate in distinct transcription regulation mechanisms.

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Abstract LB-96: Id1 enhances RING1b E3 ubiquitin ligase activity through the Mel-18/Bmi-1 polycomb group complex

10.1158/1538-7445.am10-lb-96 ◽

2010 ◽

Author(s):

Tingting Qian ◽

Jeong-Yeon Lee ◽

Hyun-Jun Kim ◽

Gu Kong

Keyword(s):

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Polycomb Group ◽

Ubiquitin Ligase Activity

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Structural insights into the interactions of Polycomb Repressive Complex 2 with chromatin

Biochemical Society Transactions ◽

10.1042/bst20210450 ◽

2021 ◽

Author(s):

Akhil Gargey Iragavarapu ◽

Liqi Yao ◽

Vignesh Kasinath

Keyword(s):

Target Genes ◽

Histone H3 ◽

Cell Type ◽

Methyltransferase Activity ◽

Post Translational Modifications ◽

Polycomb Repressive Complex 2 ◽

Polycomb Proteins ◽

Polycomb Repressive Complexes ◽

Structural Insights ◽

Stimulation Of

Polycomb repressive complexes are a family of chromatin modifier enzymes which are critical for regulating gene expression and maintaining cell-type identity. The reversible chemical modifications of histone H3 and H2A by the Polycomb proteins are central to its ability to function as a gene silencer. PRC2 is both a reader and writer of the tri-methylation of histone H3 lysine 27 (H3K27me3) which serves as a marker for transcription repression, and heterochromatin boundaries. Over the last few years, several studies have provided key insights into the mechanisms regulating the recruitment and activation of PRC2 at Polycomb target genes. In this review, we highlight the recent structural studies which have elucidated the roles played by Polycomb cofactor proteins in mediating crosstalk between histone post-translational modifications and the recruitment of PRC2 and the stimulation of PRC2 methyltransferase activity.

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Herpes Simplex Virus Type 1 ICP0 Phosphorylation Mutants Impair the E3 Ubiquitin Ligase Activity of ICP0 in a Cell Type-Dependent Manner

Journal of Virology ◽

10.1128/jvi.01063-08 ◽

2008 ◽

Vol 82 (21) ◽

pp. 10647-10656 ◽

Cited By ~ 20

Author(s):

Chris Boutell ◽

Roger Everett ◽

Joshua Hilliard ◽

Priscilla Schaffer ◽

Anne Orr ◽

...

Keyword(s):

Herpes Simplex ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Transient Transfection ◽

Dependent Manner ◽

Cell Type ◽

Ubiquitin Ligase Activity ◽

A Cell ◽

Simplex Virus

ABSTRACT Herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) is a 110-kDa nuclear phosphoprotein that is required for both the efficient initiation of lytic infection and the reactivation of quiescent viral genomes from latency. The ability of ICP0 to act as a potent viral transactivator is mediated by its N-terminal zinc-binding RING finger domain. This domain confers E3 ubiquitin ligase activity to ICP0 and is required for the proteasome-dependent degradation of a number of cellular proteins during infection, including the major nuclear domain 10 (ND10) constituent protein promyelocytic leukemia. In previous work we mapped three phosphorylation regions within ICP0, two of which directly affected its transactivation capabilities in transient transfection assays (Davido et al., J. Virol. 79:1232-1243, 2005). Because ICP0 is a phosphoprotein, we initially sought to test the hypothesis that phosphorylation regulates the E3 ubiquitin ligase activity of ICP0. Although none of the mutations affected ICP0 E3 ligase activity in vitro, transient transfection analysis indicated that mutations within one or more of the phosphorylated regions impaired the ability of ICP0 to form foci with colocalizing conjugated ubiquitin and to disrupt ND10. Mutations within one of the regions also affected ICP0 stability, and all of these phenomena occurred in a cell type-dependent manner. In the context of viral infection, only one ICP0 phosphorylation mutant (P1) showed a significant defect in viral replication and enhanced protein stability compared to all the other viruses tested. This study suggests that specific cellular environments and context of expression (transfection versus infection) differentially regulate several activities of ICP0 related to its E3 ubiquitin ligase activity via phosphorylation.

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