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Somatic Cancer Mutations in the SUV420H1 Protein Lysine Methyltransferase Modulate Its Catalytic Activity

Alexander Bröhm¹, Hany Elsawy², Philipp Rathert¹

¹Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, Stuttgart University, Allmandring 31, 70569 Stuttgart, Germany.

Journal of Molecular Biology

|July 1, 2019

Abstract:

SUV420H1 is a protein lysine methyltransferase that introduces di- and trimethylation of H4K20 and is frequently mutated in human cancers. We investigated the functional effects of eight somatic cancer mutations on SUV420H1 activity in vitro and in cells. One group of mutations (S255F, K258E, A269V) caused a reduction of the catalytic activity on peptide and nucleosome substrates. The mutated amino acids have putative roles in AdoMet binding and recognition of H4 residue D24. Group 2 mutations (E238V, D249N, E320K) caused a reduction of activity on peptide substrates, which was partially recovered when using nucleosomal substrates. The corresponding residues could have direct or indirect roles in peptide and AdoMet binding, but the effects of the mutations can be overcome by additional interactions between SUV420H1 and the nucleosome substrate. The third group of mutations (S283L, S304Y) showed enhanced activity with peptide substrates when compared with nucleosomal substrates, suggesting that these residues are involved in nucleosomal interaction or allosteric activation of SUV420H1 after nucleosome binding. Group 2 and 3 mutants highlight the role of nucleosomal contacts for SUV420H1 regulation in agreement with the high activity of this enzyme on nucleosomal substrates. Strikingly, seven of the somatic cancer mutations studied here led to a reduction of the catalytic activity of SUV420H1 in cells, suggesting that SUV420H1 activity might have a tumor suppressive function. This could be explained by the role of H4K20me2/3 in DNA repair, suggesting that loss or reduction of SUV420H1 activity could contribute to a mutator phenotype in cancer cells.

Insights

Cancer mutations in SUV420H1, a protein lysine methyltransferase, often reduce its activity. This suggests SUV420H1 may suppress tumors by maintaining H4K20 methylation crucial for DNA repair.

Area of Science:

Biochemistry and Molecular Biology
Cancer Biology
Epigenetics

Background:

SUV420H1 is a key enzyme in epigenetic regulation, catalyzing H4K20 di- and trimethylation.
Mutations in SUV420H1 are frequently observed in human cancers, implying its role in tumorigenesis.

Purpose of the Study:

To investigate the functional impact of eight somatic cancer mutations on SUV420H1 enzyme activity.
To elucidate the mechanisms by which these mutations affect SUV420H1's interaction with substrates and its overall catalytic function.

Main Methods:

In vitro enzymatic assays using peptide and nucleosome substrates.
Cell-based assays to assess the activity of mutated SUV420H1 in a cellular context.
Analysis of mutation effects on substrate binding (AdoMet, H4K20) and nucleosome interactions.

Main Results:

Mutations were categorized into three groups based on their effects on catalytic activity.
Group 1 mutations (S255F, K258E, A269V) significantly reduced activity on both peptide and nucleosome substrates.
Group 2 mutations (E238V, D249N, E320K) reduced peptide activity but showed partial recovery with nucleosomal substrates, indicating nucleosome interaction can compensate.
Group 3 mutations (S283L, S304Y) exhibited enhanced peptide activity relative to nucleosome activity, suggesting roles in nucleosome binding or allosteric regulation.
Seven of eight mutations decreased SUV420H1 activity in cells, pointing to a potential tumor suppressive role.

Conclusions:

SUV420H1 activity is sensitive to specific cancer mutations, affecting its catalytic function and substrate interactions.
Nucleosome binding plays a critical role in regulating SUV420H1 activity, with some mutations impacting this interaction.
Reduced SUV420H1 activity in cancer cells suggests a tumor suppressive function, potentially linked to H4K20 methylation's role in DNA repair and genomic stability.

Read full analysis

Keywords:

H4K20 methylation histone methylation protein lysine methylation protein lysine methyltransferase somatic cancer mutations

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