Abstract
In the last few years, the discovery of lysine and arginine methylation in histones and other proteins and the enzymes that carry out these posttranslational modifications has added a new dimension to the signal transduction field. In particular, there has been a huge surge in our understanding of how methylation of nucleosomal histones at specific lysine or arginine residues affects chromatin conformations and either facilitates or inhibits transcription from neighboring genes. It appears that the responsible methyltransferases can be targeted in some cases to specific genes and in other cases to broader regions of euchromatin or heterochromatin. Methylation of histones is mechanistically linked to other types of histone modifications, such as acetylation, phosphorylation, and monoubiquitylation; combinations of these modifications cooperate to regulate chromatin structure and transcription by stimulating or inhibiting binding of specific proteins. Although lysine methylation has thus far been observed almost exclusively on histones, arginine methylation has been observed on a variety of other proteins associated with gene regulation, including DNA-binding transcriptional activators, transcriptional coactivators, and many RNA binding proteins involved in RNA processing, transport, and stability. Thus, lysine and arginine methylation of proteins, like many other types of posttranslational modifications, are regulated steps of many specific signaling pathways.
Highlights
It would not be surprising to find a whole range of other proteins that are methylated on lysine residues; a similar experimental trend occurred with protein acetylation that was initially characterized primarily on histones but later recognized as a posttranslational modification for many nonhistone proteins (30 –33)
Structures of the conserved core region have been published for Hmt1 [149], PRMT3 [150], and PRMT1 [133], in some cases in complex with S-adenosylhomocysteine (AdoHcy; the product remaining after a methyl group is extracted from AdoMet) and/or some substrate peptides
The methylation of signal transducer and activator of transcription 1 (STAT1) appears to complement the phosphorylation of STAT1 by Jak kinases, which occurs as a result of interferon receptor activation; phosphorylation potentiates the nuclear translocation of STAT1 and its binding to its cognate enhancer element, whereas methylation prevents binding of the inhibitory protein Protein inhibitor of activated STAT1 (PIAS1)
Summary
Functional implications of methylation of individual lysine residues of histones D. Effects of arginine methylation on protein function C. First Published Online October 12, 2004 Abbreviations: AdoHcy, S-Adenosylhomocysteine; AdoMet, Sadenosyl-l-methionine; CARM1, coactivator-associated arginine methyltransferase-1; CBP, CREB-binding protein; CREB, cAMP response element binding protein; CTD, C-terminal domain; E(z), enhancer of zeste; GRIP1, glucocorticoid receptor-interacting protein-1; HMT, histone methyltransferase; hnRNP, heterogeneous nuclear ribonucleoprotein; HP1, heterochromatin protein 1; LPS, lipopolysaccharide; mAM, a murine activating transcription factor-associated modulator; NGF, nerve growth factor; NuRD, nucleosome remodeling and deacetylase; Pc, polycomb; pCAF, p300/CBP-associated factor; PEV, position effect variegation; PIAS1, protein inhibitor of activated STAT1; PRC1, polycomb repressive complex-1; PRMT, protein arginine methyltransferase; Rb, retinoblastoma; rDNA, ribosomal DNA; RNAi, RNA interference; RNA pol II, RNA polymerase II; SET, su(var), Enhancer of zeste, trithorax; shRNA, short heterochromatic RNA; SMN, survival of motor neuron; snRNPs, small nuclear ribonucleoprotein particles; STAT, signal transducer and activator of transcription; TRR, TRX-related; TRX, trithorax; Ubx, ultrabithorax. Endocrine Reviews is published bimonthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community
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