Lysine methylation steps into another step of the central dogma

Lysine methylation is an important protein modification that regulates replication and transcription, the fundamental events of the central dogma.However, whether it plays a role in translation, the last step of the central dogma, remains unclear.Two recent studies revealed that lysine methyltransferase SMYD5 catalyzes the trimethylation of lysine 22 in ribosomal protein RPL40, enhances translation output, and promotes cancer progression.Lysine methylation occurs on various proteins and the most well-studied substrates are histones.Therefore, the roles of histone lysine methylation in DNA replication, transcription, DNA repair, and DNA recombination have been extensively studied. 1 Researches on non-histone lysine methylation events and their primary functions in modulating protein-protein interactions also gradually evolved.Non-histone lysine methylation has been implicated in numerous cellular processes, such as the regulation of protein stability, promoter binding, and subcellular localization. 2ibosomal proteins are among the most abundant proteins in the cell.Several lysine methylation events at various ribosomal proteins, including RPL40, RPL4, RPL29, and RPL36A, have been documented. [3][4]4][5] However, whether lysine methylation in ribosomal protein regulates translation, the ultimate function of the ribosome, remains unclear, most likely due to the lack of identified lysine methyltransferases specific to ribosomal proteins.Two recent articles made an important breakthrough in this direction, 6,7 and insights from these studies will shed light on this underappreciated, but potentially highly important area.Employing different methodologies, the above two studies reached the same conclusion that SMYD5 methylates the core ribosomal protein RPL40.Miao et al. 6 utilized an in vitro methyltransferase assay to screen for SET domain-containing lysine methyltransferase capable of modifying the RPL40 protein.By contrast, Park et al. 7 purified recombinant SMYD5 and conducted in vitro methyltransferase assays on cellular extracts from wild-type and SMYD5-depleted cells, searching for a bona fide substrate of SMYD5 through mass spectrometry analysis.Their findings indicate that RPL40 is the predominant substrate for SMYD5, and SMYD5 appears to be the sole enzyme responsible for RPL40 K22 methylation.Notably, RPL40 K22 is almost fully methylated in multiple cell lines and animal tissues, suggesting that RPL40 K22me3 is likely a constitutive event, which implies its functional importance.It is interesting to ask whether such an