Histone H2A and H4 N-terminal Tails Are Positioned by the MEP50 WD Repeat Protein for Efficient Methylation by the PRMT5 Arginine Methyltransferase

Burgos, Emmanuel S.; Wilczek, Carola; Onikubo, Takashi; Bonanno, J.B.; Jansong, Janina; Reimer, Ulf; Shechter, David

doi:10.1074/jbc.m115.636894

Cited by 80 publications

(86 citation statements)

References 50 publications

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“…*P < 0.05; **P < 0.005; ***P < 0.0005 (2- N-P) or affect PRMT5 expression levels or cellular localization (Supplemental Figure 3, Q and R), we asked whether SHARPIN influences the formation of PRMT5/MEP50 multiprotein complexes. In support of this possibility, there is biochemical and structural evidence that PRMT5 activity can be elevated by multiprotein complex formation (20,21). This is consistent with our observation that SHARPIN enhanced intramolecular interactions between the PRMT5 N and C termini (Supplemental Figure 3G) and that endogenous SHARPIN coeluted with the endogenous PRMT5 complex (~500 kDa; Figure 4, B and C, and Supplemental Figure 3B).…”

Section: Sharpin Expression and Importance In Melanomasupporting

confidence: 79%

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Tamiya¹,

Kim²,

Klymenko³

et al. 2017

Journal of Clinical Investigation

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Section: Sharpin Expression and Importance In Melanomasupporting

confidence: 79%

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Tamiya¹,

Kim²,

Klymenko³

et al. 2017

Journal of Clinical Investigation

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“…We could not derive complete knockdown lines, consistent with an essential role for the complex in cell viability (Supplemental Figure S1C). PRMT5 knockdown caused loss of MEP50 expression while MEP50 knockdown caused PRMT5 loss, confirming the obligate pairing of these proteins 4, 22 . Both proteins were found primarily in the cytoplasm (Figure 1G).…”

Section: Resultsmentioning

confidence: 61%

“…PRMT5 is always complexed with the WD-repeat protein MEP50 to bind and orient substrate to the catalytic site to preferentially produce monomethylarginine 4, 22, 52, 53 . Elevated PRMT5 and MEP50 are found in many solid and blood cancers and often correlated with enhanced tumor growth and poor disease prognosis 2, 9, 23, 32, 43, 47 .…”

Section: Introductionmentioning

confidence: 99%

A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression

et al. 2016

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Protein arginine methyltransferase 5 (PRMT5) complexed with MEP50/WDR77 catalyzes arginine methylation on histones and other proteins. PRMT5-MEP50 activity is elevated in cancer cells and its expression is highly correlated with poor prognosis in many human tumors. We demonstrate that PRMT5-MEP50 is essential for transcriptional regulation promoting cancer cell invasive phenotypes in lung adenocarcinoma, lung squamous cell carcinoma and breast carcinoma cancer cells. RNA-Seq transcriptome analysis demonstrated that PRMT5 and MEP50 are required to maintain expression of metastasis and Epithelial-to-mesenchymal transition (EMT) markers and to potentiate an epigenetic mechanism of the TGFβ response. We show that PRMT5-MEP50 activity both positively and negatively regulates expression of a wide range of genes. Exogenous TGFβ promotes EMT in a unique pathway of PRMT5-MEP50 catalyzed histone mono- and dimethylation of chromatin at key metastasis suppressor and EMT genes, defining a new mechanism regulating cancer invasivity. PRMT5 methylation of histone H3R2me1 induced transcriptional activation by recruitment of WDR5 and concomitant H3K4 methylation at targeted genes. In parallel, PRMT5 methylation of histone H4R3me2s suppressed transcription at distinct genomic loci. Our decoding of histone methylarginine at key genes supports a critical role for complementary PRMT5-MEP50 transcriptional activation and repression in cancer invasion pathways and in response to TGFβ stimulation and therefore and orients future chemotherapeutic opportunities.

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“…The progressive distalization of Prmt5 expression and its absence from chondrogenic condensates indicates that Prmt5 is largely restricted to undifferentiated limb bud mesoderm. We noted a similar trend for the expression domain of Mep50 (Wdr77), a co-factor that regulates the function of PRMT5 (Antonysamy et al, 2012;Burgos et al, 2015;Saha et al, 2016) (Fig. S1).…”

Section: Resultsmentioning

confidence: 63%

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

Norrie

et al. 2016

Development

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During embryonic development, undifferentiated progenitor cells balance the generation of additional progenitor cells with differentiation. Within the developing limb, cartilage cells differentiate from mesodermal progenitors in an ordered process that results in the specification of the correct number of appropriately sized skeletal elements. The internal pathways by which these cells maintain an undifferentiated state while preserving their capacity to differentiate is unknown. Here, we report that the arginine methyltransferase PRMT5 has a crucial role in maintaining progenitor cells. Mouse embryonic buds lacking PRMT5 have severely truncated bones with wispy digits lacking joints. This novel phenotype is caused by widespread cell death that includes mesodermal progenitor cells that have begun to precociously differentiate into cartilage cells. We propose that PRMT5 maintains progenitor cells through its regulation of Bmp4. Intriguingly, adult and embryonic stem cells also require PRMT5 for maintaining pluripotency, suggesting that similar mechanisms might regulate lineage-restricted progenitor cells during organogenesis.

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Histone H2A and H4 N-terminal Tails Are Positioned by the MEP50 WD Repeat Protein for Efficient Methylation by the PRMT5 Arginine Methyltransferase

Cited by 80 publications

References 50 publications

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

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