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

By K. Sone, Lianhua Piao, Makoto Nakakido, K. Ueda, T. Jenuwein, Yusuke Nakamura, Ryuji Hamamoto. 2014

106 citations recorded by the source corpus.

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. γ-H2AX The Ser139 phosphorylated form of H2AX, γ-H2AX, is generated in response to DNA double-strand breaks and is involved in the repair process. Here, Sone et al.show that H2AX K134 methylation by SUV39H2 is crucial for the production of γ-H2AX, and that loss of methylation correlates with radio- and chemosensitivity.

Subfields: Molecular Biology

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Citations in the corpus

The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells (2020, unknown): “For example, our previous study reported that histone methyltransferase suppressor of variegation 3‐9 homolog 2 methylates histone H2AX and regulates H2AX phosphorylation during DNA repair (7).”
Dysregulation of AKT Pathway by SMYD2-Mediated Lysine Methylation on PTEN (2015, methodology): “Cells were transfected with FuGENE6 or Fugene HD (Promega, Fitchburg, WI) according to the manufacturer’s protocols [17,18].”
Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer (2017, unknown): “For example, we reported that the histone methyltransferase SUV39H2 induced cell proliferation and chemo- and radioresistance in lung cancer cells [7].”
PRMT1 promotes mitosis of cancer cells through arginine methylation of INCENP (2015, methodology): “Cells were transfected with FuGENE HD (Promega, Fitchburg, WI) according to manufacturer’s protocols [38].”
WHSC1L1 drives cell cycle progression through transcriptional regulation of CDC6 and CDK2 in squamous cell carcinoma of the head and neck (2016, unknown): “The number of viable cells was measured using the Cell Counting Kit-8 (Dojindo, Kumamoto, Japan) on day 6 [24].”
Critical roles of SMYD2-mediated β-catenin methylation for nuclear translocation and activation of Wnt signaling (2017, methodology): “In vitro methyltransferase assays were performed as described previously [19, 20].”
Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization (2017, methodology): “Cells were transfected with FuGENE® HD (Promega; Madison, WI) transfection reagent according to the manufacturer’s recommendations [22].”
SUV39H2 methylates and stabilizes LSD1 by inhibiting polyubiquitination in human cancer cells (2015, background): “As mentioned above, we previously reported that overexpression of SUV39H2 in various cancer types such as non-small cell lung cancer, bladder cancer and prostate cancer [23].”