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Molecular basis for substrate recruitment to the PRMT5 methylosome

ABSTRACT: PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP null cancers. PRMT5 utilizes adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1 and COPR5) and show it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable to other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosome assembly complexes. Further, disruption of this site affects Sm spliceosome stability and activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface leads to a hypomorphic decrease in growth of MTAP null tumor cells in vitro and in vivo, and is thus a novel site for development of therapeutic inhibitors of PRMT5.

ORGANISM(S): Homo sapiens

PROVIDER: GSE177036 | GEO | 2021/06/12

REPOSITORIES: GEO

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Repression of PRMT5-mediated dimethylation stabilizes vimentin and promotes metastasis in MTAP-loss lung cancer

Project description:Abstract The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis, and patients with low MTAP expression displayed worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduced the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. Vimentin was revealed as a novel dimethyl-protein with less dimethylation level in response to MTAP loss. The sDMA modification on vimentin reduces its protein abundance and trivially affects its filamentous structure. In MTAP-loss cells, lower sDMA level prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin, contributing to cell invasion. This inverse association of the MTAP/PRMT5 axis with vimentin proteins was clinically corroborated. Taken together, we propose a novel mechanism of vimentin post-translational regulation and provide new insights in metastasis.

2022-05-31 | PXD031192 | Pride

MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer

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Project description:Molecular basis for substrate recruitment to the PRMT5 methylosome

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Project description:Goal: To determine total PRMT5 methyl substrates and those that function through the novel substrate adaptor binding site

2022-06-13 | PXD019991 | Pride

Effect of PRMT5 inhibitor on gene expression in MTAP null pancreatic cell lines

Project description:Effect of PRMT5 inhibitor on gene expression in MTAP null pancreatic cell lines

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TDRD6 mediates early steps of spliceosome maturation in primary spermatocytes

Project description:Very little is known about splicing and its regulation in germ cells, particularly during meiosis. This paper describes the role of a male germ cell-specific protein, Tudor containing protein 6 (TDRD6), in assembly of the spliceosome in spermatocytes. We show that in spermatocytes, TDRD6 interacts with the key protein methyl transferase of the splicing pathway PRMT5. PRMT5 methylates arginines in substrate proteins. In a methylation dependent manner, TDRD6 also associates with spliceosomal core protein SmB in the absence of RNA, thus before an RNP-type spliceosome has been assembled. In Tdrd6-/- primary spermatocytes, PRMT5's association with SmB and the arginine dimethylation of SmB are much reduced. Abrogation of arginine methylation impaired the assembly of spliceosomes and the presence of the spliceosomal RNA U5 is aberrantly increased. These deficiencies in spliceosome maturation correlated with decreased numbers of Cajal bodies and gems involved in later stages, i.e. nuclear snRNP maturation. To reveal functional consequences of these deficiencies, transcriptome analysis of primary spermatocytes showed high numbers of splicing defects such as aberrant usage of intron and exons as well as aberrant representation of splice junctions upon TDRD6 loss. This study reveals a novel function of TDRD6 in spliceosome maturation and mRNA splicing in spermatocytes.

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