PRMT3 interacts with ALDH1A1 and regulates gene-expression by inhibiting retinoic acid signaling

Abstract

Protein arginine methyltransferase 3 (PRMT3) regulates protein functions by introducing asymmetric dimethylation marks at the arginine residues in proteins. However, very little is known about the interaction partners of PRMT3 and their functional outcomes. Using yeast-two hybrid screening, we identified Retinal dehydrogenase 1 (ALDH1A1) as a potential interaction partner of PRMT3 and confirmed this interaction using different methods. ALDH1A1 regulates variety of cellular processes by catalyzing the conversion of retinaldehyde to retinoic acid. By molecular docking and site-directed mutagenesis, we identified the specific residues in the catalytic domain of PRMT3 that facilitate interaction with the C-terminal region of ALDH1A1. PRMT3 inhibits the enzymatic activity of ALDH1A1 and negatively regulates the expression of retinoic acid responsive genes in a methyltransferase activity independent manner. Our findings show that in addition to regulating protein functions by introducing methylation modifications, PRMT3 could also regulate global gene expression through protein-protein interactions.

Unravelling Mechanisms of Doxorubicin-Induced Toxicity in 3D Human Intestinal Organoids

“…In turn, upregulation of p53, apart from the already described effects on oxidative stress and cell cycle mechanisms, upregulates RGCC, a response associated with DNA damage that suppresses cell cycle progression [54]; inhibits THBS1, an inhibitor of angiogenesis processes [31]; and downregulates MCM5, involved in DNA replication. Similarly, impairment of signalling by retinoic acid, essential for cell growth and stem cell differentiation [55], was also observed after comparing the omics data since the DEGs involved, namely DHSR9 and ALDH1A1, were found downregulated [47]. Moreover, membrane transporters of lipids and glucose were found to be perturbed as well.…”

“…Regarding the proteomics side, 19 in silico proteins were found associated with DOXinduced intestinal toxicity, the majority being involved in DOX metabolism and elimination, with few exceptions such as ALDH1A1, TOP2A, and NOLC1, as they are involved in cell growth, differentiation, and proliferation processes [47,48]. Comparison between proteomic and transcriptomic responses resulted in a summary of DOX-induced effects presented in Figure 6, starting from the entering of DOX into the cell to its elimination, through metabolism and generating the drug's different metabolites, with consequent formation of radical oxygen species (ROS), and negative effects in several biological processes.…”

Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A

“…To examine whether PRMT3 catalytic activity confers altered HCC glycolysis and growth, we conducted further studies using PRMT3‐wild‐type (WT) and catalytic inactive mutant PRMT3‐E338Q (Figure 5A). 28,29 We found that the catalytic activity of PRMT3 was critical for PRMT3‐mediated ADMA modification of LDHA, because overexpression of PRMT3‐WT led to a significant increase in ADMA signals of LDHA, whilst the catalytic inactive mutant of PRMT3 was incapable to confer such change in ADMA modification of LDHA (Figure 5B). Functional experiments results demonstrated that cells overexpressing catalytic inactive mutant of PRMT3 showed a partial decrease in cell proliferation and glycolysis activity, compared with those overexpressing WT PRMT3, as evidenced by weaker cell proliferation activities, less glucose consumption and lactate production, as well as less ECAR (Figure 5C–H).…”

Comprehensive Analysis of Aldehyde Dehydrogenases (ALDHs) and Its Significant Role in Hepatocellular Carcinoma

“…In order to have a full grasp of the ALDHs family gene function, the substrates and products of ALDHs family were summarized (Table 1 ). Literature resources are as follows: ALDH4A1 (Pemberton and Tanner 2013 ), ALDH7A1 (Bok et al 2007 ), ALDH1A1 (Verma et al 2021 ), ALDH1A2 (Verma et al 2021 ), ALDH1A3 (Verma et al 2021 ), ALDH2 (Amanuma et al 2015 ), ALDH1L1 (Krupenko et al 2019 ), ALDH1B1 (Stagos et al 2010 ), ALDH3B2 (Yin 2017 ), ALDH8A1 (Singh et al 2015 ), ALDH6A1 (Kedishvili et al 1992 ), ALDH16A1 (Vasiliou et al 2013 ), ALDH3A1, ALDH3A2, ALDH3B1, ALDH5A1, ALDH7A1, ALDH9A1, ALDH18A1 (Koppaka et al 2012 ). In addition, the phylogenetic tree of ALDHs family was structured (Fig.…”