Recognition of cancer mutations in histone H3K36 by epigenetic writers and readers

Abstract

Histone posttranslational modifications control the organization and function of chromatin. In particular, methylation of lysine 36 in histone H3 (H3K36me) has been shown to mediate gene transcription, DNA repair, cell cycle regulation, and pre-mRNA splicing. Notably, mutations at or near this residue have been causally linked to the development of several human cancers. These observations have helped to illuminate the role of histones themselves in disease and to clarify the mechanisms by which they acquire oncogenic properties. This perspective focuses on recent advances in discovery and characterization of histone H3 mutations that impact H3K36 methylation. We also highlight findings that the common cancer-related substitution of H3K36 to methionine (H3K36M) disturbs functions of not only H3K36me-writing enzymes but also H3K36me-specific readers. The latter case suggests that the oncogenic effects could also be linked to the inability of readers to engage H3K36M.

Keywords: H3K36M; Histone; PTM; cancer; methylation.

Figure 1.

Histone lysine PTMs and oncogenic mutations. (a) Schematic representation of writers, readers and erasers targeting lysine residues in histone tails of the nucleosome. (b) Residues of the H3 tail and mutations that have been linked to cancer are colored green and red, respectively.

Figure 2.

Structural basis for entrapping H3K36M in the SETD2 active site. (a) The crystal structure of the SETD2 catalytic domain (SET in white and Post-SET in pink) in complex with the H3K36M peptide (orange) and SAH (blue). SETD2 CD is shown in a surface model with the K36M-binding pocket residues and the G34-binding site residues colored yellow and light green, respectively. (b) A close view of the ribbon diagram of the H3K36M-CD-SAH complex structure. PDB ID code: 5JJY [70].

Figure 3.

Oncohistone mutations impact binding of the H3K36me3 readers. (a, b) Superimposed ¹H,¹⁵N HSQC spectra of PHF1 Tudor (a) and BRPF1 PWWP (b) recorded while H3H36me3, H3K36M and H3G34WK36me3 (residues 28–40 of H3.3) peptides were added stepwise. The spectra are color coded according to protein:peptide molar ratio. The structures of the H3K36me3-bound PHF1 Tudor domain and H3K36me3-bound BRPF1 PWWP domain are shown as surface models with the K36M-binding pocket residues and the G34-binding site residues colored yellow and light green, respectively. PDB ID codes: 4HCZ and 2X4X.