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Histone H3 Mutations: An Updated View of Their Role in Chromatin Deregulation and Cancer

1
Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38112, USA
2
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2052, Australia
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 660; https://doi.org/10.3390/cancers11050660
Received: 23 April 2019 / Revised: 3 May 2019 / Accepted: 6 May 2019 / Published: 13 May 2019
(This article belongs to the Collection Histone Modification in Cancer)
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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. View Full-Text
Keywords: histone H3.3; mutation; K27M; K36M; K9M; G34R; G34V; G34W; diffuse intrinsic pontine glioma; giant cell tumor of bone; chondroblastoma; chondrosarcoma; PRC2; SETD2 histone H3.3; mutation; K27M; K36M; K9M; G34R; G34V; G34W; diffuse intrinsic pontine glioma; giant cell tumor of bone; chondroblastoma; chondrosarcoma; PRC2; SETD2
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Lowe, B.R.; Maxham, L.A.; Hamey, J.J.; Wilkins, M.R.; Partridge, J.F. Histone H3 Mutations: An Updated View of Their Role in Chromatin Deregulation and Cancer. Cancers 2019, 11, 660.

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