ING3 is required for ATM signaling and DNA repair in response to DNA double strand breaks.
Inhibitor of Growth 3 (ING3) is a candidate tumor suppressor gene whose expression is lost in tumors such as hepatocellular carcinoma, head and neck squamous cell carcinoma and melanoma. In the present study, we show that ING3-depleted human cells and yeast cells deleted for its ortholog YNG2 are sensitive to ... DNA damage suggesting a conserved role in response to such stress. In human cells, ING3 is recruited to DNA double strand breaks and is required for ATM activation. Remarkably, in response to doxorubicin, ATM activation is dependent on ING3 but not on TIP60, whose recruitment to DNA breaks also depends on ING3. These events lead to ATM-mediated phosphorylation of NBS1 and the subsequent recruitment of RNF8, RNF168, 53BP1, and BRCA1, which are major mediators of the DNA damage response. Accordingly, upon genotoxic stress, DNA repair by non-homologous end joining (NHEJ) or homologous recombination (HR) were impaired in absence of ING3. Finally, immunoglobulin class switch recombination (CSR), a physiological mechanism requiring NHEJ repair, was impaired in the absence of ING3. Since deregulation of DNA double strand break repair is associated with genomic instability, we propose a novel function of ING3 as a caretaker tumor suppressor involved in the DNA damage signaling and repair.
Mesh Terms:
A549 Cells, Acetyltransferases, Animals, Antibiotics, Antineoplastic, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Cell Line, Tumor, DNA, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA-Binding Proteins, Doxorubicin, Enzyme Activation, Genomic Instability, Homeodomain Proteins, Humans, Immunoglobulin Class Switching, Lysine Acetyltransferase 5, Mice, RNA Interference, RNA, Small Interfering, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, Tumor Suppressor Proteins, Tumor Suppressor p53-Binding Protein 1, Ubiquitin-Protein Ligases
A549 Cells, Acetyltransferases, Animals, Antibiotics, Antineoplastic, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Cell Line, Tumor, DNA, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA-Binding Proteins, Doxorubicin, Enzyme Activation, Genomic Instability, Homeodomain Proteins, Humans, Immunoglobulin Class Switching, Lysine Acetyltransferase 5, Mice, RNA Interference, RNA, Small Interfering, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, Tumor Suppressor Proteins, Tumor Suppressor p53-Binding Protein 1, Ubiquitin-Protein Ligases
Cell Death Differ
Date: Nov. 01, 2019
PubMed ID: 30804473
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