Polycomb Group Targeting through Different Binding Partners of RING1B C-Terminal Domain

Wang, Renjing; Taylor, Alexander B.; Leal, Belinda Z.; Chadwell, Linda V.; Ilangovan, Udayar; Robinson, Angela K.; Schirf, Virgil; Hart, P. John; Lafer, Eileen M.; Demeler, Borries; Hinck, Andrew P.; McEwen, Donald G.; Kim, Chongwoo A.

doi:10.1016/j.str.2010.04.013

Cited by 85 publications

(103 citation statements)

References 67 publications

(85 reference statements)

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“…NUPR1 is not the sole IDP capable of interacting with C-RING1B, because also RYBP protein binds to it (19,20,24,25). The main physicochemical difference between RYBP and NUPR1 is that the former self-associates (both are IDPs, DNA-binding proteins with a high isoelectric point).…”

Section: Discussionmentioning

confidence: 99%

“…The main physicochemical difference between RYBP and NUPR1 is that the former self-associates (both are IDPs, DNA-binding proteins with a high isoelectric point). We know that the C-terminal domain of RYBP becomes ordered upon binding to C-RING1B (25), but from the NMR spectra of NUPR1 (Fig. 4A), NUPR1 remained disordered.…”

Section: Discussionmentioning

confidence: 99%

“…The monomeric CBX domains are also partially disordered in the absence of C-RING1B (24), but they seem to fold upon binding (25). The fact that the chemical shifts in the spectra of C-RING1B were not altered upon addition of NUPR1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The X-ray structures of C-RING1B with CBX [3GS2 (25)] and the C-terminal region of RYBP [3IXS (25)] show that any of the latter proteins pack against the side chains of Val229, Pro234, Tyr247, Ile248, Thr250, Ala254, His258, Leu259, Tyr262, Val265, and Pro324, together with electrostatic interactions involving Glu227, Arg247, Lys249, and Arg266 (25) of C-RING1B. Many of these residues were observed to interact with NUPR1 in our in silico models (discussed above).…”

Section: Structural Determinants Of the C-ring1b/nupr1 Interaction Inmentioning

confidence: 99%

“…Furthermore, we have also shown that C-RING1B is capable of interacting with RING1 and YY1 binding protein (RYBP) (19,20), which is a highly basic, oligomeric, intrinsically disordered protein (IDP) that interacts with DNA (19) and other proteins involved in apoptosis (21)(22)(23). The CBX proteins binding to C-RING1B undergo a tightening in their structures (24), and their presence hampers RYBP binding (25). Taken together, these results suggest that C-RING1B could be involved in binding to different partners, acting as a modulator of several protein cascades.…”

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confidence: 99%

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Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Santofimia‐Castaño

Rizzuti

Pey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotes, and they are often associated with diseases in humans. The protein NUPR1 is a multifunctional IDP involved in chromatin remodeling and in the development and progression of pancreatic cancer; however, the details of such functions are unknown. Polycomb proteins are involved in specific transcriptional cascades and gene silencing. One of the proteins of the Polycomb complex is the Ring finger protein 1 (RING1). RING1 is related to aggressive tumor features in multiple cancer types. In this work we characterized the interaction between NUPR1 and the paralogue RING1B in vitro, in silico, and in cellulo. The interaction occurred through the C-terminal region of RING1B (C-RING1B), with an affinity in the low micromolar range (∼10 μM). The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch at the 30s region of its sequence, as pinpointed by computational results and site-directed mutagenesis at Ala33. The association between C-RING1B and wild-type NUPR1 also occurred in cellulo as tested by protein ligation assays; this interaction is inhibited by trifluoperazine, a drug known to hamper binding of wild-type NUPR1 with other proteins. Furthermore, the Thr68Gln and Ala33Gln/Thr68Gln mutants had a reduction in the binding toward C-RING1B as shown by in vitro, in silico, and in cellulo studies. This is an example of a well-folded partner of NUPR1, because its other interacting proteins are also unfolded. We hypothesize that NUPR1 plays an active role in chromatin remodeling and carcinogenesis, together with Polycomb proteins.G ene expression control occurs through the combined activities of transcription factors and chromatin regulators, considered as effectors of epigenetic mechanisms. Posttranslational modifications of nucleosomal histones, DNA methylation, local compaction, and long-range interactions determine a variety of chromatin structures that can affect the transcriptional output.A group of chromatin regulators are the Polycomb Repressive complexes (PRCs) (1, 2). These Polycomb group (PcG) proteins are encoded by genes initially discovered over 60 years ago as repressors of the Hox genes in Drosophila (3). The PcG proteins form two main silencing heteromeric complexes called PRC1 and PRC2; both are highly conserved in eukaryotes and either in isolation or synergistically can silence genes (4, 5). The catalytic functions of both complexes include ubiquitin-ligase (H3K119ub1) and methyltransferase activity (H3K27Me3), respectively. In mammals, the PRC2 core is formed by, at least, four heteromeric units, one of which is EZH2 (or its paralog, EZH1), the methyltransferase that catalyzes the trimethylation of histone H3 at Lys27 (5). This modification can act as an anchoring site of PRC1 complexes containing chromobox (CBX) proteins. These CBX proteins recruit PRC1 complex onto PRC2-enriched chromatin, facilitating the monoubiquitylation. The PRC1-dependent monoubiquitylation at Lys119 of histone H2A correlates with transc...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Structural Determinants Of the C-ring1b/nupr1 Interaction Inmentioning

confidence: 99%

mentioning

confidence: 99%

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Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Santofimia‐Castaño

Rizzuti

Pey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Topology and enzymatic properties of a canonical Polycomb repressive complex 1 isoform

2019

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Polycomb repressive complex 1 (PRC1) catalyses monoubiquitination of histone H2A on Lys119, promoting gene silencing. Cells at different developmental stages and in different tissues express different PRC1 isoforms. The topology, subunit composition, structural architecture and molecular mechanism of most of these isoforms are still poorly characterized. Here, we have purified a PRC1 isoform comprising subunits RING1B, PCGF2, CBX2 and PHC2, two stable subcomplexes (RING1B‐PCGF2 and RING1B‐PHC2) and the catalytic subunit RING1B in isolation. By crosslinking mass spectrometry, we identified novel interactions between RING1B and the three non‐catalytic subunits. Biochemical, biophysical, and enzymatic data suggest that CBX2 and PHC2 play a structural role, whereas PCGF2 also modulates catalysis. Our data offer insights into the molecular architecture of PRC1 and its histone ubiquitination activity.

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Cell Fate and Developmental Regulation Dynamics by Polycomb Proteins and 3D Genome Architecture

2019

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Targeted transitions in chromatin states at thousands of genes are essential drivers of eukaryotic development. Therefore, understanding the in vivo dynamics of epigenetic regulators is crucial for deciphering the mechanisms underpinning cell fate decisions. This review illustrates how, in addition to its cell memory function, the Polycomb group of transcriptional regulators orchestrates temporal, cell and tissue‐specific expression of master genes during development. These highly sophisticated developmental transitions are dependent on the context‐ and tissue‐specific assembly of the different types of Polycomb Group (PcG) complexes, which regulates their targeting and/or activities on chromatin. Here, an overview is provided of how PcG complexes function at multiple scales to regulate transcription, local chromatin environment, and higher order structures that support normal differentiation and are perturbed in tumorigenesis.

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Polycomb Group Targeting through Different Binding Partners of RING1B C-Terminal Domain

Cited by 85 publications

References 67 publications

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Topology and enzymatic properties of a canonical Polycomb repressive complex 1 isoform

Cell Fate and Developmental Regulation Dynamics by Polycomb Proteins and 3D Genome Architecture

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