Protein function is controlled by many factors and can be dictated by the distinct array of modifications that occur after proteins are synthesized. Modifications that are unique to specific diseases can inform about the origin of the disease and provide a platform for designing treatment strategies.With the recent publication of two high-impact research papers, biochemist and cancer biologist Yingming Zhao, PhD, professor of the Ben May Department for Cancer Research at the University of Chicago, is charting new territory in the understanding of post-translational modifications by describing novel ‘marks’ on histones and metabolic enzymes.
Histones are the protein components of nucleosomes upon which DNA is wound and compacted in the nucleus in chromatin. A wide array of histone modifications has been identified, and their presence or absence alters the accessibility of genes to the transcriptional machinery and subsequent gene expression.
Frequently, tumor cells have different levels or patterns of histone marks compared to their normal cell counterparts. Not only can these modifications serve as biomarkers of cancer, but they also may provide therapeutic opportunities, as there are drugs available that prevent many of these marks from forming.
Zhao and collaborators from France recently reported in Nature Chemical Biology the identification of a new histone modification on lysine residues called lysine 2-hydroxyisobutyrylation (Khib).
Using mass spectrometry and validation with chemical and biochemical methodology, this histone mark was identified at many sites, including several not known to be modified in other ways.
The investigators found that this histone mark was distributed across the genome differently than other well-characterized histone lysine modifications, and that the modification was conserved among species, widely distributed and induced major chromatin structural changes.
Although the team focused their analyses on gene regulation in sperm development, it is likely that this new lysine modification will impact other cellular processes and may have an important role in disease.
In another collaborative study published in the most recent issue of Cell Metabolism, Dr. Zhao and his group describe a new protein posttranslational modification called lysine glutarylation (Kglu).
They discovered this alteration on certain proteins through approaches similar to those described above, and characterized an enzyme called sirtuin 5 (SIRT5) as being responsible for removing this modification from specific target proteins.
SIRT5 is annotated as a regulator of another protein modification, acetylation, and is one of several sirtuins linked to cancer, aging, diabetes and metabolism.
The researchers also characterized an important protein that is modified with Kglu as carbamoyl phosphate synthase (CPS1) – the rate-limiting enzyme in the urea cycle that controls ammonia detoxification primarily in the liver.
Importantly, this work sheds new light into the mechanisms responsible for a genetic disease caused by mutations in glutaryl CoA dehydrogenase called glutaric acidemia type I. These findings also broaden our understanding of SIRT5 and lay the foundation for future work by this group and others in defining the function of Kglu modifications in diseases such as cancer.