Year: 2023
Type: article
Abstract: Perez and Sarkies uncover histones as methyl group repositories in normal and cancer human cells, shedding light on an intriguing function of histone methylation in optimizing the cellular methylation potential independently of gene regulation.S-adenosylmethionine (SAM) functions as the major methyl donor for numerous cellular reactions and processes including DNA, RNA and protein methylation, amino acid metabolism, nucleotide synthesis, neurotransmitter synthesis, and more.SAM's role is facilitated by its readily available methyl group (CH 3 ) for transfer in various methylation reactions catalysed by methyltransferase enzymes [1].The utilization of SAM by methyltransferases generates the by-product S-adenosylhomocysteine (SAH).SAH competes with SAM for binding to methyltransferase enzymes and can inhibit the enzyme's ability to carry out further methylation reactions.SAH itself can undergo further metabolism: it can be recycled through the methionine cycle to regenerate SAM or directed into the transsulfuration pathway, supporting the synthesis of sulfur-containing compounds such as cysteine and glutathione (Fig 1) [1].Consequently, the SAM/SAH ratio is a critical parameter that reflects the cellular capacity for methylation reactions as well as the metabolic pathways reliant on SAH.Balancing the SAM/SAH ratio hinges partly on substrates capable of accepting SAM's methyl group, known as "methylation sinks" (Fig 1).Notable reactions that involve SAM utilization and result in its diminished levels include the synthesis of 1-methylnicotinamide (1MNA) from nicotinamide (NA) via nicotinamide N-methyltransferase (NNMT), and the conversion of phosphatidylethanolamine (PE) into phosphatidylcholine (PC) by phosphatidylethanolamine methyltransferase (PEMT) [2].Histones, boasting numerous lysine residues susceptible to methylation and an array of histone methyltransferases (HMTs), have been demonstrated as methyl sinks in budding yeast, particularly under conditions of impaired phospholipid methylation [3].However, the question of whether histones fulfill a comparable role in other eukaryotes, including human cells, remained unanswered.In this issue, Perez and Sarkies [4] adeptly leverage a substantial body of published data to demonstrate that histones indeed function as alternative methyl sinks to NA and PE in human cells (Fig 1).Their first key insight came from correlating the expression of HMTs with metabolite levels in cancer datasets.This analysis unveiled 1MNA as the most negatively correlated
Source: PLoS Biology
Institution: University of California, Los Angeles
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,500
Awards: G1538217767, G7568158682, G9000285914
OpenAlex ID: W4387970600