MEPCE

Last update 23 Jan 2025

Basic Info

Synonyms

7SK snRNA methylphosphate capping enzyme, BCDIN3, Bicoid-interacting protein 3 homolog

+ [4]

Introduction

S-adenosyl-L-methionine-dependent methyltransferase that adds a methylphosphate cap at the 5'-end of 7SK snRNA (7SK RNA), leading to stabilize it (PubMed:17643375, PubMed:19906723, PubMed:30559425). Also has a non-enzymatic function as part of the 7SK RNP complex: the 7SK RNP complex sequesters the positive transcription elongation factor b (P-TEFb) in a large inactive 7SK RNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation (PubMed:17643375). The 7SK RNP complex also promotes snRNA gene transcription by RNA polymerase II via interaction with the little elongation complex (LEC) (PubMed:28254838). In the 7SK RNP complex, MEPCE is required to stabilize 7SK RNA and facilitate the assembly of 7SK RNP complex (PubMed:19906723). MEPCE has a non-enzymatic function in the 7SK RNP complex; interaction with LARP7 within the 7SK RNP complex occluding its catalytic center (PubMed:19906723).

100 Clinical Results associated with MEPCE

100 Translational Medicine associated with MEPCE

0 Patents (Medical) associated with MEPCE

Literatures (Medical) associated with MEPCE

01 Dec 2024·Molecular Cell

The phosphatase PP1 sustains global transcription by promoting RNA polymerase II pause release

Article

Author: Luo, Yi-Qing ; Chen, Fei Xavier ; Shang, Xue-Ying ; Xiao, Ruijing ; Wang, Zhenning ; Danko, Charles G ; Yin, Zhinang ; Wang, Jingwen ; Miao, Maojian ; Hu, Shibin ; Zhou, Xinwen ; Liang, Kaiwei ; Tao, Bolin ; Song, Aixia

RNA polymerase II progression from initiation to elongation is driven in part by a cascade of protein kinases acting on the core transcription machinery. Conversely, the corresponding phosphatases, notably PP2A and PP1-the most abundant serine-threonine phosphatases in cells-are thought to mainly impede polymerase progression, respectively restraining pause release at promoters and elongation at terminators. Here, we reveal an unexpected role of PP1, within the phosphatase 1 nuclear targeting subunit (PNUTS)-PP1 complex, in sustaining global transcriptional activation in human cells. Acute disruption of PNUTS-PP1 leads to severe defects in the release of paused polymerase and subsequent downregulation for the majority of transcribed genes. PNUTS-PP1 promotes pause release by dephosphorylating multiple substrates, including the 7SK small nuclear ribonucleoprotein particle (snRNP) subunit MEPCE, a known pausing regulator. PNUTS-PP1 exhibits antagonistic functions compared with Integrator-PP2A (INTAC) phosphatase, which generally inhibits pause release. Our research thus highlights opposing roles of PP1 and PP2A in modulating genome-wide transcriptional pausing and gene expression.

19 Jan 2024·ACS Chemical Biology

Comparative Analysis of Two NNMT Bisubstrate Inhibitors through Chemoproteomic Studies: Uncovering the Role of Unconventional SAM Analogue Moiety for Improved Selectivity

Article

Author: Iyamu, Iredia D ; Meng, Ying ; Huang, Rong ; Ahmed, Noha A M

Unconventional S-adenosyl-L-methionine (SAM) mimics with enhanced hydrophobicity are an adaptable building block to develop cell-potent inhibitors for SAM-dependent methyltransferases as targeted therapeutics. We recently discovered cell-potent bisubstrate inhibitors for nicotinamide N-methyltransferase (NNMT) by using an unconventional SAM mimic. To delve into the selectivity implications of the unconventional SAM mimic, we employed a chemoproteomic approach to assess two potent NNMT inhibitors LL320 (K_i, app = 6.8 nM) and II399 (containing an unconventional SAM mimic, K_i, app = 5.9 nM) within endogenous proteomes. Our work began with the rational design and synthesis of immobilized probes 1 and 2, utilizing LL320 and II399 as parent compounds. Systematic analysis of protein networks associated with these probes revealed a comprehensive landscape. Notably, NNMT emerged as the top-ranking hit, substantiating the high selectivity of both inhibitors. Meanwhile, we identified additional interacting proteins for LL320 (38) and II399 (17), showcasing the intricate selectivity profiles associated with these compounds. Subsequent experiments confirmed LL320's interactions with RNMT, DPH5, and SAHH, while II399 exhibited interactions with SHMT2 and MEPCE. Importantly, incorporating the unconventional SAM mimic in II399 led to improved selectivity compared to LL320. Our findings underscore the importance of selectivity profiling and validate the utilization of the unconventional SAM mimic as a viable strategy to create highly selective and cell-permeable inhibitors for SAM-dependent methyltransferases.

03 Jan 2024·GENETICS

Catalytic activity of the Bin3/MePCE methyltransferase domain is dispensable for 7SK snRNP function in Drosophila melanogaster

Article

Author: Palumbo, Ryan J ; Hanes, Steven D ; Feigon, Juli ; Yang, Yuan

AbstractMethylphosphate Capping Enzyme (MePCE) monomethylates the gamma phosphate at the 5′ end of the 7SK noncoding RNA, a modification thought to protect 7SK from degradation. 7SK serves as a scaffold for assembly of a snRNP complex that inhibits transcription by sequestering the positive elongation factor P-TEFb. While much is known about the biochemical activity of MePCE in vitro, little is known about its functions in vivo, or what roles—if any—there are for regions outside the conserved methyltransferase domain. Here, we investigated the role of Bin3, the Drosophila ortholog of MePCE, and its conserved functional domains in Drosophila development. We found that bin3 mutant females had strongly reduced rates of egg-laying, which was rescued by genetic reduction of P-TEFb activity, suggesting that Bin3 promotes fecundity by repressing P-TEFb. bin3 mutants also exhibited neuromuscular defects, analogous to a patient with MePCE haploinsufficiency. These defects were also rescued by genetic reduction of P-TEFb activity, suggesting that Bin3 and MePCE have conserved roles in promoting neuromuscular function by repressing P-TEFb. Unexpectedly, we found that a Bin3 catalytic mutant (Bin3Y795A) could still bind and stabilize 7SK and rescue all bin3 mutant phenotypes, indicating that Bin3 catalytic activity is dispensable for 7SK stability and snRNP function in vivo. Finally, we identified a metazoan-specific motif (MSM) outside of the methyltransferase domain and generated mutant flies lacking this motif (Bin3ΔMSM). Bin3ΔMSM mutant flies exhibited some—but not all—bin3 mutant phenotypes, suggesting that the MSM is required for a 7SK-independent, tissue-specific function of Bin3.

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