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Nat Commun. 2014 Dec 9;5:5691. doi: 10.1038/ncomms6691.

Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair.

Author information

1
Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, Illinois 60637, USA.
2
Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
3
Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, D-79108 Freiburg, Germany.
4
1] Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, Illinois 60637, USA [2] Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

Abstract

The presence of phosphorylated histone H2AX (γ-H2AX) is associated with the local activation of DNA-damage repair pathways. Although γ-H2AX deregulation in cancer has previously been reported, the molecular mechanism involved and its relationship with other histone modifications remain largely unknown. Here we find that the histone methyltransferase SUV39H2 methylates histone H2AX on lysine 134. When H2AX was mutated to abolish K134 methylation, the level of γ-H2AX became significantly reduced. We also found lower γ-H2AX activity following the introduction of double-strand breaks in Suv39h2 knockout cells or on SUV39H2 knockdown. Tissue microarray analyses of clinical lung and bladder tissues also revealed a positive correlation between H2AX K134 methylation and γ-H2AX levels. Furthermore, introduction of K134-substituted histone H2AX enhanced radio- and chemosensitivity of cancer cells. Overall, our results suggest that H2AX methylation plays a role in the regulation of γ-H2AX abundance in cancer.

PMID:
25487737
PMCID:
PMC4268694
DOI:
10.1038/ncomms6691
[Indexed for MEDLINE]
Free PMC Article

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