Hierarchical assembly of the MLL1 core complex regulates H3K4 methylation and is dependent on temperature and component concentration

Namitz, Kevin E.W.; Tan, Song; Cosgrove, Michael S.

doi:10.1016/j.jbc.2023.102874

Cited by 3 publications

(15 citation statements)

References 78 publications

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“…We recently characterized the hydrodynamic and kinetic properties of the catalytic module of the human MLL1 core complex reconstituted with MLL1 residues 3745 to 3969, which is the minimal SET domain fragment required for complex assembly ( 17 , 29 ) ( Fig. 1 B ).…”

Section: Resultsmentioning

confidence: 99%

“…1 B ). We found that the disassembled state of the MLL1 core complex is favored at physiological temperature (37 °C), which results in irreversible enzyme inactivation and low catalytic activity ( 17 ). Since increased protein concentration partially restores enzymatic activity, we tested whether the catalytic module of the MLL1 core complex may be regulated by inducing high local concentrations via liquid-liquid phase separation (LLPS).…”

Section: Resultsmentioning

confidence: 99%

“…We previously showed that MWRAD 2 is hierarchically assembled from MW and RAD 2 subcomplexes ( 17 ). To confirm that the droplets contain both subcomplexes, we assembled MWRAD 2 complexes where representative members of the MW and RAD 2 subcomplexes (WDR5 and RbBP5) were labeled with FITC, which did not appreciably disrupt assembly or enzymatic activity of the complexes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4 B ). The reaction in each state is modeled assuming a nonprocessive reaction in which the monomethyl product is released from the E1 active site, which then binds to the second active site (E2) within the complex for the di-methylation reaction, as described previously ( 17 ). Turnover numbers ( k cat ) for the mono- and di-methylation reactions were assumed to be identical for each state of the enzyme and were fixed, allowing estimation of the catalytic efficiency ( k cat /K m ) for each reaction.…”

Section: Resultsmentioning

confidence: 99%

“…1 B ). In a previous investigation, we showed that the MLL1 core complex is hierarchically assembled from MW and RAD 2 subcomplexes in an interaction that is highly concentration- and temperature-dependent ( 17 ). Intriguingly, we found that the disassembled state of the MLL1 core complex is favored at physiological temperature and that increased protein concentration partially overcomes this thermodynamic barrier for complex assembly.…”

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confidence: 99%

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Phase separation promotes a highly active oligomeric scaffold of the MLL1 core complex for regulation of histone H3K4 methylation

Namitz,

Showalter,

Cosgrove

2023

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Phase separation promotes a highly active oligomeric scaffold of the MLL1 core complex for regulation of histone H3K4 methylation

Namitz,

Showalter,

Cosgrove

2023

Journal of Biological Chemistry

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A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance

Hao,

Huang,

Hua

et al. 2023

PLoS Biol

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The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem–like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up–regulated in CRC CSCs (cCSCs) expansion and chemo–resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to −261 to −141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri–methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem–like traits and chemoresistance to CRC by co–regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo–resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3–WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem–like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2–deregulated tumors.

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Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders

Gurung,

Om,

Pun

et al. 2023

Cancers

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WD40-repeat (WDR) domain proteins play a crucial role in mediating protein–protein interactions that sustain oncogenesis in human cancers. One prominent example is the interaction between the transcription factor MYC and its chromatin co-factor, WD40-repeat domain protein 5 (WDR5), which is essential for oncogenic processes. The MYC family of proteins is frequently overexpressed in various cancers and has been validated as a promising target for anticancer therapies. The recruitment of MYC to chromatin is facilitated by WDR5, highlighting the significance of their interaction. Consequently, inhibiting the MYC–WDR5 interaction has been shown to induce the regression of malignant tumors, offering an alternative approach to targeting MYC in the development of anticancer drugs. WDR5 has two protein interaction sites, the “WDR5-binding motif” (WBM) site for MYC interaction and the histone methyltransferases SET1 recognition motif “WDR5-interacting” (WIN) site forming MLL complex. Significant efforts have been dedicated to the discovery of inhibitors that target the WDR5 protein. More recently, the successful application of targeted protein degradation technology has enabled the removal of WDR5. This breakthrough has opened up new avenues for inhibiting the interaction between WDR5 and the binding partners. In this review, we address the recent progress made in targeting WDR5 to inhibit MDR5–MYC and MDR5–MLL1 interactions, including its targeted protein degradation and their potential impact on anticancer drug discovery.

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Hierarchical assembly of the MLL1 core complex regulates H3K4 methylation and is dependent on temperature and component concentration

Cited by 3 publications

References 78 publications

Phase separation promotes a highly active oligomeric scaffold of the MLL1 core complex for regulation of histone H3K4 methylation

Phase separation promotes a highly active oligomeric scaffold of the MLL1 core complex for regulation of histone H3K4 methylation

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance

Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders

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