PRMTs and Arginine Methylation: Cancer’s Best-Kept Secret?

甲基化 癌症 DNA甲基化 生物 精氨酸 癌症研究 医学 计算生物学 遗传学 基因表达 基因 氨基酸
作者
James Jarrold,Clare C. Davies
出处
期刊:Trends in Molecular Medicine [Elsevier BV]
卷期号:25 (11): 993-1009 被引量:299
标识
DOI:10.1016/j.molmed.2019.05.007
摘要

Arginine methylation as a PTM has gained considerable interest since the recent discovery that solid and haematological cancers display elevated expression of PRMTs, which correlates with poor patient prognosis. Several new findings have cemented arginine methylation as a key regulator of processes hijacked by the cancer cell to ensure survival, including epigenetic-mediated gene expression, mRNA splicing, and the DNA damage response. Growing appreciation of the important role of PRMT5 in cancer stem cell function provides an exciting therapeutic prospect. The development of specific PRMT inhibitors has proceeded at an unprecedented pace, resulting in three major pharmaceutical companies entering their own PRMT inhibitors into Phase I trials. Drug targeting of arginine methylation is becoming a real clinical prospect. Post-translational modification (PTM) of proteins is vital for increasing proteome diversity and maintaining cellular homeostasis. If the writing, reading, and removal of modifications are not controlled, cancer can develop. Arginine methylation is an understudied modification that is increasingly associated with cancer progression. Consequently protein arginine methyltransferases (PRMTs), the writers of arginine methylation, have rapidly gained interest as novel drug targets. However, for clinical success a deep mechanistic understanding of the biology of PRMTs is required. In this review we focus on advances made regarding the role of PRMTs in stem cell biology, epigenetics, splicing, immune surveillance and the DNA damage response, and highlight the rapid rise of specific inhibitors that are now in clinical trials for cancer therapy. Post-translational modification (PTM) of proteins is vital for increasing proteome diversity and maintaining cellular homeostasis. If the writing, reading, and removal of modifications are not controlled, cancer can develop. Arginine methylation is an understudied modification that is increasingly associated with cancer progression. Consequently protein arginine methyltransferases (PRMTs), the writers of arginine methylation, have rapidly gained interest as novel drug targets. However, for clinical success a deep mechanistic understanding of the biology of PRMTs is required. In this review we focus on advances made regarding the role of PRMTs in stem cell biology, epigenetics, splicing, immune surveillance and the DNA damage response, and highlight the rapid rise of specific inhibitors that are now in clinical trials for cancer therapy. the addition of two methyl groups to only one of a possible two terminal guanidino nitrogen atoms of an arginine residue. a method to analyse protein interactions with DNA or histone tail modifications. the enzymatic processing of double-strand break (DSB) ends to create 3′ single-stranded DNA overhangs which are substrates for the Rad51 strand-exchange protein, ultimately leading to homologous recombination-mediated repair. a protein sequence enriched in arginine and glycine residues that is often targeted for arginine methylation. The first GAR (RG/RGG) motif described was for the nucleolin protein. the H2NC(=NH)NH− group of guanidine that constitutes the positive charge of the arginine side chain and is modified by methylation. The guanidino groups hold five potential sites for hydrogen bond formation, a number depleted by one with each methyl group added. the standardised way in which to report histone modifications. For example, H4R3me2a refers to asymmetric dimethylation (me2a) of arginine 3 (R3) within histone H4 (H4). a major repair pathway in the DDR. This mechanism uses sister chromatids as references to accurately repair damaged DNA. a cell-surface protein complex found on nucleated cells that presents foreign antigens to cytotoxic CD8+ T cells during the immune response. a heterogeneous group of age-related haematopoietic diseases which originate from changes in haematopoietic stem cell function. a type of DSB repair that involves the direct ligation of break-ends without the need of a homologous template. a methyl-donor cofactor for all methylation events in the cell. protein–RNA complexes composed of small nuclear RNA (snRNA) and seven Sm-class proteins. These structures are an important part of the spliceosome that is crucial for the removal of noncoding sequences from pre-mRNAs. the addition of one methyl group to each of the two terminal guanidino nitrogen atoms on an arginine residue. genetically similar or even identical. nucleic acid structures formed when nascent mRNA transcripts reanneal to single-stranded DNA, following the activity of RNA polymerase II. These structures displace the remaining DNA strand and have been associated with DNA DSBs and genomic instability. a domain of ∼60 amino acids that folds into four antiparallel β-strands and specifically binds to either methyl-lysine or methyl-arginine residues.
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