Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

Carlson, Scott M.; Gozani, Or

doi:10.1101/cshperspect.a026435

Cited by 100 publications

(94 citation statements)

References 112 publications

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“…Biological functions for lysine methylation is best characterized on histone proteins and the regulation of epigenetics and chromatin biology (Chi et al, 2010). Beyond histones, there is a growing appreciation that a number of non-histone proteins (e.g., p53, RB, RelA) are modulated by lysine methylation (Carlson and Gozani, 2016). In the human proteome, there are predicted to be greater than 100 KMTs that belong to one of two protein methylase families: SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain enzymes and 7bS (seven-b strand) enzymes (Clarke, 2013).…”

Section: Introductionmentioning

confidence: 99%

METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

Liu

Hausmann

Carlson

et al. 2019

Cell

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Section: Introductionmentioning

confidence: 99%

METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

Liu

Hausmann

Carlson

et al. 2019

Cell

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“…We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10)(11)(12). Finally, we are discovering how alterations in protein methylation pathways can lead to human pathology, particularly in cancer (13)(14)(15).…”

Section: Regulation Of Biological Function By Protein Methylation Reamentioning

confidence: 99%

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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Cellular physiology depends on the alteration of protein structures by covalent modification reactions. Using a combination of bioinformatic, genetic, biochemical, and mass spectrometric approaches, it has been possible to probe ribosomal proteins from the yeast Saccharomyces cerevisiae for posttranslationally methylated amino acid residues and for the enzymes that catalyze these modifications. These efforts have resulted in the identification and characterization of the first protein histidine methyltransferase, the first N-terminal protein methyltransferase, two unusual types of protein arginine methyltransferases, and a new type of cysteine methylation. Two of these enzymes may modify their substrates during ribosomal assembly because the final methylated histidine and arginine residues are buried deep within the ribosome with contacts only with RNA. Two of these modifications occur broadly in eukaryotes, including humans, while the others demonstrate a more limited phylogenetic range. Analysis of strains where the methyltransferase genes are deleted has given insight into the physiological roles of these modifications. These reactions described here add diversity to the modifications that generate the typical methylated lysine and arginine residues previously described in histones and other proteins. Regulation of biological function by protein methylation reactionsIt is more and more apparent just how much of biological function is dependent upon posttranslational modifications (1). The human genome encodes some 900 enzymes catalyzing just protein phosphorylation or ubiquitination (2,3). However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,4-8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10-12). Finally, we are discovering how alterations in protein methylation pathways can lead to human pathology, particularly in cancer (13-15).The collection of over sixty human protein arginine and lysine methyltransferases that leave histone "marks" recognized by reader proteins to guide gene expression are perhaps the poster children for the importance of protein methyltransferases (16-17). However, recent work has emphasized the importance of methylating non-histone substrates at these residues, particularly ribosomal proteins, translation factors, and transcription factors in a wide variety of organisms (7,8,15,18,19). Furthermore, the methylation of lysine and arginine residues represents just the tip of the iceberg in protein methylation -modifications have also been established at histidine, modified histidine (diphthamide), glutamate, glutamine, asparagine, Lisoaspartate, D-aspartate, cysteine, isoprenylcysteine, me...

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“…Most lysine methylation regulators localize to the nucleus at least some of the time (Figure 1) (Carlson and Gozani, 2016). However, beyond chromatin function, few studies have revealed mechanisms of lysine methylation signaling in the nucleus.…”

Section: Lysine Methylation Inside the Nucleusmentioning

confidence: 99%

“…The identification of new sites of lysine methylation has far outpaced functional annotation. In fact, only a small fraction of non-histone lysine methylation sites have been assigned a function ( Supplementary Table 1) and the majority of these studies have been limited to a few proteins (e.g., p53, ER, RB1), which have been extensively reviewed elsewhere (Biggar and Li, 2015;Biggar et al, 2017;Carlson and Gozani, 2016). Here, we discuss key findings in recent years that have expanded our understanding and appreciation of the functional role of lysine methylation in molecular processes by finetuning non-histone protein function (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Lysine Methylation Regulators Moonlighting outside the Epigenome

et al. 2019

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Landmark discoveries made nearly two decades ago identified known transcriptional regulators as histone lysine methyltransferases; since then the field of lysine methylation signaling has been dominated by studies of how this small chemical posttranslational modification regulates gene expression and other chromatin-based processes. However, recent advances in mass spectrometry-based proteomics have revealed that histones are just a subset of the thousands of eukaryotic proteins marked by lysine methylation. As the writers, erasers, and readers of histone lysine methylation are emerging as a promising therapeutic target class for cancer and other diseases, a key challenge for the field is to define the spectrum of activities for these proteins, beyond histones. Here we summarize recent discoveries implicating nonhistone lysine methylation as a major regulator of diverse cellular processes. We further discuss recent technological innovations that are enabling the expanded study of lysine methylation signaling.Collectively, these findings are shaping our understanding of the fundamental mechanisms of non-histone protein regulation through this dynamic and multi-functional posttranslational modification.

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Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

Cited by 100 publications

References 112 publications

METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Lysine Methylation Regulators Moonlighting outside the Epigenome

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