Abstract
In this review, we describe the attributes of histone H3 mutants identified in cancer. H3 mutants were first identified in genes encoding H3.3, in pediatric high-grade glioma, and subsequently in chondrosarcomas and giant cell tumors of bone (GCTB) in adolescents. The most heavily studied are the lysine to methionine mutants K27M and K36M, which perturb the target site for specific lysine methyltransferases and dominantly perturb methylation of corresponding lysines in other histone H3 proteins. We discuss recent progress in defining the consequences of these mutations on chromatin, including a newly emerging view of the central importance of the disruption of H3K36 modification in many distinct K to M histone mutant cancers. We also review new work exploring the role of H3.3 G34 mutants identified in pediatric glioma and GCTB. G34 is not itself post-translationally modified, but G34 mutation impinges on the modification of H3K36. Here, we ask if G34R mutation generates a new site for methylation on the histone tail. Finally, we consider evidence indicating that histone mutations might be more widespread in cancer than previously thought, and if the perceived bias towards mutation of H3.3 is real or reflects the biology of tumors in which the histone mutants were first identified.
Highlights
Chromatin is composed of nucleosomes and their associated proteins, with each nucleosome consisting of an octamer of two copies each of histones H3, H4, H2A, and H2B, wrapped 1.7 times by 147 bp of DNA
Given its central role in the control of cellular processes, an exquisite regulatory system of chromatin biology has evolved. This relies heavily on post-translational modification (PTM) of chromatin, at both the DNA and histone level, with an extensive array of modifications, including acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and isomerization occurring on the histone tails that protrude beyond the nucleosomal DNA, as well as on the histone cores that are wrapped by the DNA
Details of the reports differ, all have found that H3K36M peptides or nucleosomes more efficiently pull down the SETD2 H3 K36 methyltransferase or its fission yeast homolog, Set2, from cellular extracts than the wild type H3 controls [11,93,94], and that the K36M mutant dominantly inhibits the activity of SETD2, likely through this enhanced binding and sequestration of enzyme activity
Summary
Chromatin is composed of nucleosomes and their associated proteins, with each nucleosome consisting of an octamer of two copies each of histones H3, H4, H2A, and H2B, wrapped 1.7 times by 147 bp of DNA. Subsequent studies have extended the breadth of cancers known to carry mutations in H3 to include chondroblastoma, giant cell tumors of bone, chondrosarcoma, pediatric soft tissue sarcoma, head and neck squamous cell carcinoma and leukemia [7,8,9,10,11,12,13] These mutants have generated substantial interest from both basic scientists and clinicians to discern how mutation of a single allele encoding H3 can exert dominant effects to alter H3 function in cells with 30 alleles encoding H3 isoforms, and how cells bearing these mutant H3s might be targeted for therapy. Mutant H3 class, where a lysine that is normally subject to methylation or acetylation is mutated to methionine, and the glycine 34 mutant class, where mutation of G34 impacts the modification of the nearby K36 residue
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