Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Zhang, Yuxiang; Remillard, David; Onubogu, Ugoma; Karakyriakou, Barbara; Asiaban, Joshua N.; Ramos, Anissa R.; Bowland, Kirsten; Bishop, Timothy R.; Barta, Paige; Nance, Stephanie; Durbin, Adam D.; Ott, Christopher J.; Janiszewska, Michalina; Cravatt, Benjamin F.; Erb, Michael

doi:10.1038/s41594-023-01041-4

Cited by 13 publications

(6 citation statements)

References 96 publications

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“…Mutually exclusive mutation patterns suggest incompatible driver mutations in tumorigenesis, indicating a potential source of SL interactions [54] . In addition, the combination of high-throughput CRISPR-Cas9 screens with the background gene's low expression (which might be caused by mutation, copy number variation, or epigenetic modification) is also a major logic for SL pair discovery [55] , [56] , [57] . Furthermore, to understand specific SL interactions in the cellular context, it's important to consider the dynamic relationship of genes.…”

Section: Discussionmentioning

confidence: 99%

Using graph-based model to identify cell specific synthetic lethal effects

Pu,

Cheng,

et al. 2023

Computational and Structural Biotechnology Journal

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Section: Discussionmentioning

confidence: 99%

Using graph-based model to identify cell specific synthetic lethal effects

Pu,

Cheng,

et al. 2023

Computational and Structural Biotechnology Journal

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“…Identifying mutually exclusive gene pairs from tumor genomes is advantageous for discovering SL interactions[28, 56] and can be utilized in prediction models[37, 60, 61]. In addition, the combination of high-throughput CRISPR-Cas9 screens with the background gene’s low expression (which might be caused by mutation, copy number variation, or epigenetic modification) is also a major logic for SL pair discovery[5, 53, 62]. Furthermore, to understand specific SL interactions in the cellular context, it’s important to consider the dynamic relationship of genes.…”

Section: Methodsmentioning

confidence: 99%

“…To address this, it is vital to incorporate cell context-specific characterization using diverse omics data of the given cell line, including mutation profiles, gene expression patterns, and functional divergence. These data ensure the model capture the context specificity inherent to specific cell lines [5,53]. Besides, the L1000 Connectivity Map [54] provides crucial information on expression changes of representative genes in response to gene perturbations specific to a given cell line.…”

Section: Introductionmentioning

confidence: 99%

Cell context-specific Synthetic lethality Prediction and Mechanism Analysis

Xing,

Pu,

Cheng

et al. 2023

Preprint

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Synthetic lethality (SL) holds significant promise as a targeted cancer therapy by selectively eliminating tumor cells while sparing normal cells. However, the discovery of SL gene pairs has encountered tremendous challenges, including high costs and low efficiency of experimental methods. Current computational approaches only provide limited insights because of overlooking the crucial aspects of cellular context dependency and mechanistic understanding of SL pairs. To overcome these challenges, we have developed SLWise, a deep-learning model capable of predicting SL interactions in diverse cellular backgrounds. We evaluated SLWise using a real world ground truth standard. The evaluation demonstrated that SLWise outperformed benchmark models in SL prediction. Additionally, we proposed a novel analysis scheme called SLAD-CE (Synthetic Lethal Associated Gene Detection and Cell Damage Evaluation) for the identification of abnormal essential genes induced by SL gene pairs and tracking the extent of cell damage. Leveraging the cell-line-specific input feature L1000 and employing Gene Set Enrichment Analysis (GSEA), SLAD-CE provides valuable insights into the underlying mechanisms of SLWise-predicted gene pairs. The combined utilization of SLWise and SLAD-CE offers an approach for predicting and analyzing SL interactions in specific cellular contexts. Our findings highlight the potential of SLWise and SLAD-CE in advancing SL-based therapies by improving prediction accuracy and enhancing mechanistic understanding, ultimately contributing to the development of effective precision treatments for cancer.

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“…To determine the full repertoire of proteins degraded by UM171, we conducted a global proteomics analysis in two UM171-sensitive leukemia cell lines, SET-2 and MV4;11, after vehicle or UM171 treatment (6 h, 1 µM). LSD1 and two CoREST homologs, RCOR1 (hereafter referred to as CoREST) and HDAC2 partially blocked CoREST-GFP depletion by UM171, likely due to functional redundancy between the two paralogs 26 (Fig. 2a; Extended Data Fig.…”

Section: Um171 Promotes Selective Degradation Of Hdac1/2 Complexesmentioning

confidence: 99%

Asymmetric Engagement of Dimeric CRL3^KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes

Yeo,

Zhang,

Xie

et al. 2024

Preprint

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UM171 is a potent small molecule agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal, a process that is tightly controlled by epigenetic regulation. By co-opting KBTBD4, a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, UM171 promotes the degradation of members of the CoREST transcriptional corepressor complex, thereby limiting HSC attrition. However, the direct target and mechanism of action of UM171 remain unclear. Here, we reveal that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1 to promote the degradation of select HDAC1/2 corepressor complexes. Through proteomics and chemical inhibitor studies, we discover that the principal target of UM171 is HDAC1/2. Cryo-electron microscopy (cryo-EM) analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex unveils an unexpected asymmetric assembly, in which a single UM171 molecule enables a pair of KBTBD4 KELCH-repeat propeller domains to recruit HDAC1 by clamping on its catalytic domain. One of the KBTBD4 propellers partially masks the rim of the HDAC1 active site pocket, which is exploited by UM171 to extend the E3-neo-substrate interface. The other propeller cooperatively strengthens HDAC1 binding via a separate and distinct interface. The overall neomorphic interaction is further buttressed by an endogenous cofactor of HDAC1-CoREST, inositol hexakisphosphate, which makes direct contacts with KBTBD4 and acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces defined by cryo-EM is demonstrated by in situ base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, our results reveal how the cooperativity offered by a large dimeric CRL E3 family can be leveraged by a small molecule degrader and establish for the first time a dual molecular glue paradigm.

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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Cited by 13 publications

References 96 publications

Using graph-based model to identify cell specific synthetic lethal effects

Using graph-based model to identify cell specific synthetic lethal effects

Cell context-specific Synthetic lethality Prediction and Mechanism Analysis

Asymmetric Engagement of Dimeric CRL3^KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes

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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Cited by 13 publications

References 96 publications

Using graph-based model to identify cell specific synthetic lethal effects

Using graph-based model to identify cell specific synthetic lethal effects

Cell context-specific Synthetic lethality Prediction and Mechanism Analysis

Asymmetric Engagement of Dimeric CRL3KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes

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Product

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Asymmetric Engagement of Dimeric CRL3^KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes