Examples of Crosstalk Between Post-translational Modifications

Pathway Description:

Post-translational modifications (PTMs) are emerging as major effectors of protein function, and in turn, cellular processes. The discovery and investigation of post-translational modifications such as methylation, acetylation, phosphorylation, sumoylation, and many others has established both nuclear and non-nuclear roles for PTMs. With the awareness of PTMs, there is an ever-growing list of them and more and more research centered on their function. In recent years, there is an overwhelming appreciation for the diversity of modifications, but most importantly, the interplay between them. This interplay is essential for proper gene expression, genome organization, cell division and DNA damage response. PTMs can directly impact cell function by modifying histones, modifying enzymes and their associated activity, assembling protein complexes as well as recognition and targeting in the genome or to other cellular compartments. In the context of single modifications and gene expression, acetylation of certain lysines (i.e., Histone 3 lysine [9-H3K9]) correlates with activation, while tri-methylation of this same residue is most often associated with compaction and gene repression. In the case of lysine methylation, lysine can be mono-, di-, or tri-methylated; while arginine can be mono- or dimethylated in an asymmetric or symmetric fashion. Each degree of methylation for lysines and arginines serves as its own PTM and impacts biological output. Most PTMs do not exist alone in the chromatin environment and the combination of these states can reinforce one another. For example, one PTM can serve as a docking site for a binding domain called a “reader” within one protein, while another “reader” within the same protein can recognize another residue. This is the case for the reader protein BPTF, which binds both H3K4me3 and H4K16 acetylation. Therefore, modulating the various types and degrees of modifications will impact output. For these reasons, the cell has developed a series of enzymes that are important for establishing and maintaining these PTMs, which are often referred to as “writers” (e.g., histone methyltransferases, acetyltransferases, etc.) or “erasers” (e.g., histone demethylases, deacetylases, etc.). Many of these enzymes have emerged as critical therapeutic targets and have been identified as key regulators of diseases such as cancer. These observations have also made their associated PTMs candidates for biomarkers in cancer and other diseases.

Selected Reviews:

• Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447(7143), 407–12.
• Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150(1), 12–27.
• Gardner KE, Allis CD, Strahl BD (2011) Operating on chromatin, a colorful language where context matters. J. Mol. Biol. 409(1), 36–46.
• Lee JS, Smith E, Shilatifard A (2010) The language of histone crosstalk. Cell 142(5), 682–5.
• Musselman CA, Kutateladze TG (2011) Handpicking epigenetic marks with PHD fingers. Nucleic Acids Res. 39(21), 9061–71.
• Yang XJ, Seto E (2008) Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell 31(4), 449–61.

We would like to thank Prof. Johnathan Whetstine, Harvard Medical School and Massachusetts General Hospital Cancer Center, Charlestown, MA, for reviewing this diagram.