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

Kenbun Sone,Thomas Jenuwein,Koji Ueda,Yusuke Nakamura,Ryuji Hamamoto,Lianhua Piao,Makoto Nakakido

doi:10.1038/ncomms6691

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.

Highlights

The presence of phosphorylated histone H2AX (g-H2AX) is associated with the local activation of DNA-damage repair pathways
This phosphorylated form of histone H2AX is referred to as g-H2AX and is a marker of DNA damage. g-H2AX accumulates at sites of damaged chromatin within seconds of the formation of a double-strand breaks (DSBs) and triggers the accumulation of several components involved in the DNA-damage response (DDR) signalling cascade[8,9]
We demonstrate that Suppressor of Variegation 3–9 Homologue 2 (SUV39H2) methylates histone H2AX, and that the H2AX methylation is critical for g-H2AX accumulation in human cancer

Summary

Introduction

The presence of phosphorylated histone H2AX (g-H2AX) is associated with the local activation of DNA-damage repair pathways. The structural subunit of chromatin is the nucleosome, which consist of a histone octameric core constituted of four different histone types: H2A, H2B, H3 and H4 These nuclear histones can undergo a variety of chemical modifications such as acetylation, methylation, ubiquitination, sumoylation, poly ADP-ribosylation and phosphorylation[1]. When DSBs occur, H2AX accumulates near the DNA breakage sites and is quickly phosphorylated by members of the phosphatidyl-inositol-3-kinase-related kinases family, including ataxia telangiectasia-mutated (ATM), ataxia telangiectasia and Rad3-related (ATR) and DNA-activated protein kinase[7]. This phosphorylated form of histone H2AX is referred to as g-H2AX and is a marker of DNA damage. We demonstrate that SUV39H2 methylates histone H2AX, and that the H2AX methylation is critical for g-H2AX accumulation in human cancer

Methods

Results

Conclusion