JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes

Lee, Schuyler; Liu, Haolin; Hill, Ryan C.; Chen, Chunjing; Hong, Xue-Ren; Crawford, Frances; Kingsley, Molly C.; Zhang, Qianqian; Liu, Xinjian; Chen, Zhongzhou; Lengeling, Andreas; Bernt, Kathrin M.; Marrack, Philippa; Kappler, John W.; Zhou, Qiang; Li, Chuan-Yuan; Xue, Yuhua; Hansen, Kirk C.; Zhang, Gongyi

doi:10.7554/elife.53930

Cited by 25 publications

(30 citation statements)

References 53 publications

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“…super elongation complex is only a docking site for P‐TEFb. Based on our recent results, CTD of Pol II requires the help of BRD4 and JMJD6 to recruit P‐TEFb from the 7SK snRNP complex, 13 or Tat protein in HIV to hijack P‐TEFb 139 . MLL‐fusion alone is unable to recruit P‐TEFb.…”

Section: A Third Underlying the Mechanism Of Mll‐fusions To Trigger Tmentioning

confidence: 97%

“…Thus, it is essential to understand how paused Pol II is regulated in higher eukaryotes, which remains elusive to this day. In recent years, we fortuitously found that a group of orphan family members of Jumonji domain containing protein family, including JMJD5, JMJD6, and JMJD7, may work together with the super elongation complex to play critical roles in the release of paused Pol II 10‐13 (Liu et al, unpublished). The pausing of RNA Pol II at promoter regions is a unique transcription regulation mechanism seen in higher eukaryotes 48‐54 .…”

Section: Jmjd5 and Jmjd7 Cleave Arginine Methylate Histone Tails To Gmentioning

confidence: 99%

“…Interestingly, our recent characterization of the function of JMJD6 shows that the recruitment of CDK9 to the super elongation complex is tightly controlled. It appears that the super elongation complex is unlikely to recruit P‐TEFb including CDK9 and cyclin T1 without the assistance of JMJD6 and BRD4 13 . Compared with efficient recruitment of the CDK9 complex (P‐TEFb, including CDK9 and cyclin T1) by TAT protein in human immunodeficiency virus (HIV), 95 BRD4 is claimed to be responsible for the endogenous recruitment of P‐TEFb to the promoters of Pol II pausing regulated genes 96‐98 .…”

Section: Jmjd6 Cleaves Mepce To Release Cdk9 Complex (P‐tefb)mentioning

confidence: 99%

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The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

Liu

Lee

Zhang

et al. 2020

Molecular Carcinogenesis

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A majority of infant and pediatric leukemias are caused by the mixed-lineage leukemia gene (MLL) fused with a variety of candidates. Several underlying mechanisms have been proposed. One currently popular view is that truncated MLL1 fusion and its associated complex constitutively hijacks super elongation complex, including positive transcription elongation factor b, CDK9, and cyclin T1 complex and DOT1L, to enhance the expression of transcription factors that maintain or restore stemness of leukocytes, as well as prevent the differentiation of hematopoietic progenitor cells. An alternative emerging view proposes that MLL1-fusion promotes the recruitment of TATA binding protein and RNA polymerase II (Pol II) initiation complex, so as to increase the expression levels of target genes. The fundamental mechanism of both theories are gain of function for truncated MLL1 fusions, either through Pol II elongation or initiation. Our recent progress in transcription regulation of paused Pol II through JMJD5, JMJD6, and JMJD7, combined with the repressive role of H3K4me3 revealed by others, prompted us to introduce a contrarian hypothesis: the failure to shut down transcribing units by MLL-fusions triggers the transformation: loss of function of truncated MLL1 fusions coupled with the loss of conversion of H3K4me1 to H3K4me3, leading to the constitutive expression of transcription factors that are in charge of maintenance of hematopoietic progenitor cells, may trigger the transformation of normal cells into cancer cells. Following this track, a potential treatment to eliminate these fusion proteins, which may ultimately cure the disease, is proposed. K E Y W O R D S CDK9, JMJD5, JMJD6, MLL-fusion, RNA polymerase II

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Section: A Third Underlying the Mechanism Of Mll‐fusions To Trigger Tmentioning

confidence: 97%

Section: Jmjd5 and Jmjd7 Cleave Arginine Methylate Histone Tails To Gmentioning

confidence: 99%

Section: Jmjd6 Cleaves Mepce To Release Cdk9 Complex (P‐tefb)mentioning

confidence: 99%

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The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

Liu

Lee

Zhang

et al. 2020

Molecular Carcinogenesis

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“…Knockouts of JMJD6 could lead to severe defects in mice, which suggested critical roles of JMJD6 in development 35 . Furthermore, JMJD6 could accompany with BRD4 to regulate the activity of CDK9 and RNA polymerase II complex 36 . However, the specific function and therapeutic significance of JMJD6 in RCC are indefinite.…”

Section: Introductionmentioning

confidence: 99%

Epigenome screening highlights that JMJD6 confers an epigenetic vulnerability and mediates sunitinib sensitivity in renal cell carcinoma

Zhang

Huang

et al. 2021

Clinical & Translational Med

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Aberrant epigenetic reprogramming represents a hallmark of renal cell carcinoma (RCC) tumorigenesis and progression. Whether there existed other epigenetic vulnerabilities that could serve as therapeutic targets remained unclear and promising. Here, we combined the clustered regularly interspaced short palindromic repeats functional screening results and multiple RCC datasets to identify JMJD6 as the potent target in RCC. JMJD6 expression correlated with poor survival outcomes of RCC patients and promoted RCC progression in vitro and in vivo. Mechanistically, aberrant p300 led to high JMJD6 expression, which activated a series of oncogenic crosstalk. Particularly, high‐throughput sequencing data revealed that JMJD6 could assemble super‐enhancers to drive a list of identity genes in kidney cancer, including VEGFA, β‐catenin, and SRC. Moreover, this JMJD6‐mediated oncogenic effect could be suppressed by a novel JMJD6 inhibitor (SKLB325), which was further demonstrated in RCC cells, patient‐derived organoid models, and in vivo. Given the probable overlapped crosstalk between JMJD6 signature and tyrosine kinase inhibitors downstream targets, targeting JMJD6 sensitized RCC to sunitinib and was synergistic when they were combined together. Collectively, this study indicated that targeting JMJD6 was an effective approach to treat RCC patients.

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“…It has been reported to hydroxylate lysine residues and demethylate arginine residues in proteins and histones [ 6 , 7 , 8 , 9 ]. Recently, additional catalytic activities were proposed, namely a kinase and a protease function [ 10 , 11 ]. Among the substrates for JMJD6-hydroxylation activity is the U2AF 65 kDa subunit (U2AF65), a key regulator of splicing [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

JMJD6 Regulates Splicing of Its Own Gene Resulting in Alternatively Spliced Isoforms with Different Nuclear Targets

Raguz

Heim

Engal

et al. 2020

IJMS

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Jumonji-domain-containing protein 6 (JMJD6) is a Fe(II) and 2-oxogluterate (2OG) dependent oxygenase involved in gene regulation through post-translationally modifying nuclear proteins. It is highly expressed in many cancer types and linked to tumor progression and metastasis. Four alternatively-spliced jmjd6 transcripts were annotated. Here, we focus on the two most abundantly expressed ones, which we call jmjd6-2 and jmjd6-Ex5. TCGA SpliceSeq data revealed a significant decrease of jmjd6-Ex5 transcripts in patients and postmortem tissue of several tumors. The two protein isoforms are distinguished by their C-terminal sequences, which include a serine-rich region (polyS-domain) in JMJD6-2 that is not present in JMJD6-Ex5. Immunoprecipitation followed by LC-MS/MS for JMJD6-Ex5 shows that different sets of proteins interact with JMJD6-2 and JMJD6-Ex5 with only a few overlaps. In particular, we found TFIIF-associating CTD phosphatase (FCP1), proteins of the survival of motor neurons (SMN) complex, heterogeneous nuclear ribonucleoproteins (hnRNPs) and upstream binding factor (UBF) to interact with JMJD6-Ex5. Like JMJD6-2, both UBF and FCP1 comprise a polyS-domain. The polyS domain of JMJD6-2 might block the interaction with polyS-domains of other proteins. In contrast, JMJD6-2 interacts with many SR-like proteins with arginine/serine-rich (RS)-domains, including several splicing factors. In an HIV-based splicing reporter assay, co-expression of JMJD6-2 inhibited exon inclusion, whereas JMJD6-Ex5 did not have any effect. Furthermore, the silencing of jmjd6 by siRNAs favored jmjd6-Ex5 transcripts, suggesting that JMJD6 controls splicing of its own pre-mRNA. The distinct molecular properties of JMJD6-2 and JMJD6-Ex5 open a lead into the functional implications of the variations of their relative abundance in tumors.

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JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes

Cited by 25 publications

References 53 publications

The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

Epigenome screening highlights that JMJD6 confers an epigenetic vulnerability and mediates sunitinib sensitivity in renal cell carcinoma

JMJD6 Regulates Splicing of Its Own Gene Resulting in Alternatively Spliced Isoforms with Different Nuclear Targets

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