CK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site

Area of Science:

• Epigenetics and gene regulation
• Molecular biology
• Cellular mechanisms

Background:

• Polycomb repressive complex 2 (PRC2) is crucial for maintaining cell identity during differentiation.
• PRC2's methyltransferase activity on histone H3 lysine 27 (H3K27me3) is regulated by posttranslational modifications.

Purpose of the Study:

• To elucidate a novel phosphorylation-dependent mechanism that stimulates PRC2 enzymatic activity.
• To investigate the role of SUZ12 residue S583 phosphorylation in PRC2 function.

Main Methods:

• Utilized X-ray crystallography to capture the structural mechanism of phosphorylation.
• Employed biochemical assays to assess PRC2 activity, substrate binding, and reporter gene repression.
• Investigated PRC2 recruitment and H3K27me3 deposition in mouse embryonic stem cells (mESCs).

Main Results:

• Casein kinase 2 (CK2) phosphorylates SUZ12 at residue S583, enhancing PRC2 methyltransferase activity.
• Crystal structure reveals S583 phosphorylation stabilizes the PRC2 active site, particularly the S-adenosyl-methionine (SAM) binding pocket.
• Phosphorylation increases PRC2 binding to SAM and nucleosomal substrates, facilitating gene repression.
• Loss of S583 phosphorylation impairs PRC2 recruitment and H3K27me3 deposition in mESCs, compromising differentiated cell identity.

Conclusions:

• CK2-mediated S583 phosphorylation is a unique mechanism that enhances PRC2 catalytic activity and substrate binding.
• This phosphorylation is essential for PRC2's role in maintaining differentiated cell identity and H3K27me3 deposition.
• Targeting this regulatory mechanism could offer insights into epigenetic control of cell fate.