EZH2 belongs to a group of enzymes called histone methyltransferases, which modify histones, the proteins that DNA wraps around to form chromatin, the material that makes up chromosomes. Histone modifications can alter the structure of chromatin, affecting gene expression and cellular processes.
In the case of EZH2, its activity leads to the methylation of histone H3 at a specific site known as lysine 27 (H3K27me3). This modification is associated with gene silencing, and when EZH2 becomes overactive or dysregulated, it can result in the abnormal repression of tumor suppressor genes and the activation of oncogenes, promoting uncontrolled cell growth and cancer development.
The research study, conducted by scientists at the University of Cambridge and the Cancer Research UK Cambridge Institute, utilized advanced techniques, such as cryo-electron microscopy, to determine the precise structure of the EZH2 enzyme in complex with its substrate, a nucleosome (the basic unit of chromatin). This detailed understanding of the enzyme's structure and interactions with DNA and histones provides valuable insights into its catalytic mechanism.
The findings revealed that EZH2 employs a two-step mechanism for its enzymatic activity. First, it recruits and binds to specific DNA sequences through a reader module within the enzyme. This binding event brings EZH2 into close proximity with the target nucleosomes. Subsequently, the catalytic domain of EZH2 catalyzes the methylation of H3K27.
Moreover, the study identified two distinct conformations or states of EZH2 during the catalytic process. The transition between these states regulates the enzyme's activity and ensures the precise placement of H3K27me3 marks on target nucleosomes.
Additionally, the researchers explored the impact of mutations frequently found in EZH2 in cancer patients. These mutations were shown to disrupt the regulatory mechanism of the two-step enzymatic process, leading to aberrant H3K27 methylation patterns and contributing to cancer development.
The research findings provide a comprehensive molecular understanding of how the EZH2 enzyme functions and the mechanisms underlying its role in cancer. This knowledge opens up new avenues for the development of targeted therapies that specifically inhibit EZH2 activity, potentially offering promising treatment strategies for various cancer types.
