KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1

Wong, Sarah J.; Gearhart, Micah D.; Taylor, Alexander B.; Nanyes, David R.; Ha, Daniel J.; Robinson, Angela K.; Artigas, Jason A.; Lee, Oliver J.; Demeler, Borries; Hart, P. John; Bardwell, Vivian J.; Kim, Chongwoo A.

doi:10.1016/j.str.2016.07.011

Cited by 52 publications

(66 citation statements)

References 27 publications

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“…However, in leukemic cells we find that USP7 inhibition not only leads to reduced H2AK119ub but also induces loss of PRC1.1/KDM2B binding as a result of complex disassembly, suggesting that KDM2B-PCGF1-BCOR/L1/SKP1 interactions might be needed for targeting. This is in agreement with data that suggest that dimerization of PCGF1 and BCOR(L1) is required for binding to KDM2B and recruiting PRC1.1 to the chromatin [64].…”

Section: Discussionsupporting

confidence: 93%

USP7 as part of non-canonical PRC1.1 is a druggable target in leukemia

Maat

Jaques

López

et al. 2017

Preprint

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Acute myeloid leukemia (AML) is a highly heterogeneous disease in which genetic and epigenetic changes disturb regulatory mechanisms controlling stem cell fate and maintenance. AML still remains difficult to treat, in particular in poor risk AML patients carrying TP53 mutations. Here, we identify the deubiquitinase USP7 as an integral member of non-canonical PRC1.1 and show that targeting of USP7 provides an alternative therapeutic approach for AML. USP7 inhibitors effectively induced apoptosis in (primary) AML cells, also independent of the USP7-MDM2-TP53 axis, whereby survival of both the cycling as well as quiescent populations was affected. MLL-AF9-induced leukemia was significantly delayed in vivo in human leukemia xenografts. We previously showed that non-canonical PRC1.1 is critically important for leukemic stem cell self-renewal, and that genetic knockdown of the PRC1.1 chromatin binding component KDM2B abrogated leukemia development in vitro and in vivo [1]. Here, by performing KDM2B interactome studies in TP53mut cells we identify that USP7 is an essential component of PRC1.1 and is required for its stability and function. USP7 inhibition results in disassembly of the PRC1.1 complex and consequently loss of binding to its target loci. Loss of PRC1.1 binding coincided with reduced H2AK119ub and H3K27ac levels and diminished gene transcription, whereas H3K4me3 levels remained unaffected. Our studies highlight the diverse functions of USP7 and link it to Polycomb-mediated epigenetic control. USP7 inhibition provides an efficient therapeutic approach for AML, also in the most aggressive subtypes with mutations in TP53.Key pointsUSP7 is a therapeutic target in leukemia, including poor risk TP53mut AML.USP7 is an essential component of non-canonical PRC1.1 and is required for its stability and function.

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Section: Discussionsupporting

confidence: 93%

USP7 as part of non-canonical PRC1.1 is a druggable target in leukemia

Maat

Jaques

López

et al. 2017

Preprint

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“…It appears that the huge megaDalton sized protein assemblies build up in a well-defined, step by step process. First, different sub-complexes are formed, as described in the case of ncPRC1.1 [357]. It was found that KDM2B/SKP1 heterodimer can only bind to PCGF1 RAWUL domain after the formation of a PCGF1/BCORL1 heterodimer.…”

Section: The Assembly Of Ncprc1 Subunits Is Still Under Debatementioning

confidence: 99%

“…It was found that KDM2B/SKP1 heterodimer can only bind to PCGF1 RAWUL domain after the formation of a PCGF1/BCORL1 heterodimer. The BCORL1 PUFD domain preceding the RAWUL domain produces the extended interface only after heterodimer formation for interaction of the preformed KDM2B/SKP1 sub-complex [357]. Subsequently, the complex grows even larger after contacting the RING1 (or RNF2) and RYBP/YAF2 module.…”

Section: The Assembly Of Ncprc1 Subunits Is Still Under Debatementioning

confidence: 99%

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

2018

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Originally two types of Polycomb Repressive Complexes (PRCs) were described, canonical PRC1 (cPRC1) and PRC2. Recently, a versatile set of complexes were identified and brought up several dilemmas in PRC mediated repression. These new class of complexes were named as non-canonical PRC1s (ncPRC1s). Both cPRC1s and ncPRC1s contain Ring finger protein (RING1, RNF2) and Polycomb group ring finger catalytic (PCGF) core, but in ncPRCs, RING and YY1 binding protein (RYBP), or YY1 associated factor 2 (YAF2), replaces the Chromobox (CBX) and Polyhomeotic (PHC) subunits found in cPRC1s. Additionally, ncPRC1 subunits can associate with versatile accessory proteins, which determine their functional specificity. Homozygous null mutations of the ncPRC members in mice are often lethal or cause infertility, which underlines their essential functions in mammalian development. In this review, we summarize the mouse knockout phenotypes of subunits of the six major ncPRCs. We highlight several aspects of their discovery from fly to mice and emerging role in target recognition, embryogenesis and cell-fate decision making. We gathered data from stem cell mediated in vitro differentiation assays and genetically engineered mouse models. Accumulating evidence suggests that ncPRC1s play profound role in mammalian embryogenesis by regulating gene expression during lineage specification of pluripotent stem cells.

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“…Variant PRC1 accessory proteins can also provide unique functionality to the PRC1 complexes. For example, the H3K36me2 demethylase, KDM2, interacts with the variant BCOR complex and recruits the complex to CPG islands [32, 77, 78]. Beyond ubiquitination, PRC1 complexes repress gene activity by chromatin compaction [20, 33, 92].…”

Section: Polycomb H2a Ubiquitinationmentioning

confidence: 99%

“…Besides skeletal transformations, Asxl1 −/− mice exhibit microphthalmia, craniofacial dysmorphisms and myelodysplasia but have not been described as microcephalic [33, 75–77]. Asxl2 −/− mice showed enlarged hearts with interstitial fibrosis and cardiomyocyte disarray and do not exhibit macrocephaly [73, 78]. This discrepancy in brain size phenotypes between mice and humans is an interesting observation that warrants further analysis, as the role for PR-DUB function in brain development has not yet been described.…”

Section: H2aub1 Deubiquitination Syndromesmentioning

confidence: 99%

Histone H2A Monoubiquitination in Neurodevelopmental Disorders

2017

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Covalent histone modifications play an essential role in gene regulation and cellular specification required for multicellular organism development. Mono-ubiquitination of histone H2A (H2AUb1) is a reversible transcriptionally repressive mark. Exchange of histone H2A mono-ubiquitination and deubiquitination reflects the succession of transcriptional profiles during development required to produce cellular diversity from pluripotent cells. Germline pathogenic variants in components of the H2AUb1 regulatory axis are being identified as the genetic basis of congenital neurodevelopmental disorders. Here, we review the human genetics findings coalescing on molecular mechanisms that alter the genome-wide distribution of this histone modification required for development.

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KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1

Cited by 52 publications

References 27 publications

USP7 as part of non-canonical PRC1.1 is a druggable target in leukemia

USP7 as part of non-canonical PRC1.1 is a druggable target in leukemia

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

Histone H2A Monoubiquitination in Neurodevelopmental Disorders

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