Summary Using an integrated approach, we here report the identification of 67 novel histone marks, a discovery that increases the current number of known histone marks by about 70%. We verified one of the newly-identified marks, lysine crotonylation (Kcr), as a novel, evolutionarily-conserved histone post-translational modification. The unique structure and genomic localization of Kcr suggest that it is mechanistically and functionally different from lysine acetylation (Kac), a previously-described post-translational modification. Specifically, in both human somatic and mouse male germ cell genomes, histone Kcr marks either active promoters or potential enhancers. In male germinal cells immediately following meiosis, Kcr is enriched on sex chromosomes and specifically marks testis-specific genes, including a significant proportion of X-linked genes that escape sex chromosome inactivation in haploid cells. These results therefore dramatically extend the repertoire of histone PTM sites and designate Kcr as a specific mark of active sex chromosome-linked genes in post-meiotic male germ cells.
Protein post-translational modifications (PTMs) at the lysine residue, such as lysine methylation, acetylation, and ubiquitination, are diverse, abundant, and dynamic. They play a key role in the regulation of diverse cellular physiology. Here we report discovery of a new type of lysine PTM, lysine malonylation (Kmal). Kmal was initially detected by mass spectrometry and protein sequence-database searching. The modification was comprehensively validated by Western blot, tandem MS, and high-performance liquid chromatography of synthetic peptides, isotopic labeling, and identification of multiple Kmal substrate proteins. Kmal is a dynamic and evolutionarily conserved PTM observed in mammalian cells and bacterial cells. In addition, we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo. This result suggests the possibility of nondeacetylation activity of other class III lysine deacetylases, especially those without obvious acetylation protein substrates. Our results therefore reveal a new type of PTM pathway and identify the first enzyme that can regulate lysine malonylation and lysine succinylation status. Molecular & Cellular Proteomics 10: 10.1074/ mcp.M111.012658, 1-12, 2011.Cellular function and physiology are largely determined by the inventory of all proteins in a cell, its proteome. The collection and characterization of the proteome is critical to understanding cellular mechanisms and diseases. Proteomes in eukaryotic cells consist of over a million molecular species of proteins, easily orders of magnitude more complex than the corresponding genomes (1, 2). There are two major mechanisms for expanding the coding capacity of the human genome: mRNA splicing and protein post-translational modifications (PTMs)1 . PTMs (more than 300 types) are complex and fundamental mechanisms of cellular regulation, and have been associated with almost all known cellular pathways and disease processes (1, 2). As an example, protein phosphorylation, the most well-studied PTM, is present in more than one third of human proteins, the phosphorylation status of which can potentially be regulated by ϳ500 human protein kinases and ϳ150 phosphatases (3, 4). The modification mainly occurs at several amino acid residues: serine, threonine, tyrosine, and histidine. Protein phosphorylation makes its substrate residues more acidic, hydrophilic, and induces a charge change from ϩ1 charge to -1 (at physiological pH), which in turn modulates the structure and functions of substrate proteins.The high complexity of PTMs is also reflected by diverse modifications at -amine group of lysine residue, including methylation, acetylation, and ubiquitination. These lysine PTMs have been shown to play an important role in cellular regulations (5, 6). Recently, we identified a new type of PTM at lysine residues, lysine succinylation (7). Like phosporylation, lysine succinylation also induces a change of two negative charges in lysine re...
The combination of high-density transposon-mediated mutagenesis and high-throughput sequencing has led to significant advancements in research on essential genes, resulting in a dramatic increase in the number of identified prokaryotic essential genes under diverse conditions and a revised essential-gene concept that includes all essential genomic elements, rather than focusing on protein-coding genes only. DEG 10, a new release of the Database of Essential Genes (available at http://www.essentialgene.org), has been developed to accommodate these quantitative and qualitative advancements. In addition to increasing the number of bacterial and archaeal essential genes determined by genome-wide gene essentiality screens, DEG 10 also harbors essential noncoding RNAs, promoters, regulatory sequences and replication origins. These essential genomic elements are determined not only in vitro, but also in vivo, under diverse conditions including those for survival, pathogenesis and antibiotic resistance. We have developed customizable BLAST tools that allow users to perform species- and experiment-specific BLAST searches for a single gene, a list of genes, annotated or unannotated genomes. Therefore, DEG 10 includes essential genomic elements under different conditions in three domains of life, with customizable BLAST tools.
Despite of the progress in identifying many Lysine (Lys)1 acetylation is a dynamic, reversible, and evolutionarily conserved protein post-translational modification (PTM). After the discovery of Lys acetylation in histones more than forty years ago (1), early studies mainly focused on histones and transcription factors, establishing the modification's fundamental role in DNA-templated biological processes (2, 3). The discovery of Lys acetylation in tubulin and the presence of sirtuins in mitochondria argued that Lys acetylation may not be restricted to nuclei (4 -6). The complexity of Lys acetylomes outside the nuclei and the high abundance of the PTM in mitochondria revealed by proteomics studies suggested that the regulatory functions of this PTM may mirror those of protein phosphorylation (7-9).Lys acetylation is regulated by two groups of enzymes with opposing activities, lysine acetyltransferases and deacetylases (10). Sirtuins are a family of highly conserved NAD ϩ -dependent deacetylases (11,12). Numerous studies, mainly focusing on the family's founding member, SIRT1 in mammals or Sir2, the enzyme's homolog in yeast, show that sirtuins regulate diverse cellular functions and appear to affect a variety of aging-related diseases, such as cancer, metabolic diseases, and inflammation and are involved in pathways such as metabolisms, oxidative stress, DNA damage, cell cycle, and signaling (12-15). A number of protein substrates for SIRT1 have been identified including p53, DNA methyltransferase 1 (DNMT1), NF-B, forkhead transcription factors, PGC-1␣, and histones (16 -22). Despite significant progress in the past decade, the molecular mechanisms by which SIRT1 regulates cellular physiology are not well understood. A major hurdle in our understanding of SIRT1 biology is our incomplete knowledge of Lys acetylation proteins that mediate SIRT1 functions. Because SIRT1 is a lysine deacetylase, a major mechanism for SIRT1 to exert its functions should be its deacetylation activity. However, SIRT1-induced lysine acetylation proteins are far from complete. This knowledge limitation also exists with other deacetylases as well as with lysine acetyltransferases, representing a major challenge in Lys acetylation biology and in evaluating clinical compounds that target dysregulated Lysacetylation regulatory enzymes.Here we report the first proteomics quantification of Lys acetylation in response to a regulatory enzyme. Our study identified 4623 Lys acetylation sites from SIRT1 ϩ/ϩ and SIRT1 Ϫ/Ϫ MEF cells, among which 4130 Lys acetylation sites were quantified. The data identified multiple pathways that are affected by SIRT1. From this wealth of new information on the SIRT1-modulated Lys acetylome, we discovered consensus motifs for SIRT1-mediated Lys acetylation sites and identified extensive correlation between Lys acetylation and phosphorylation, SUMOylation, and mutations associated with disease,
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