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Updated: Jan 28, 2026
Analysis of DNA Double-strand Break DSB Repair in Mammalian Cells
Published on: September 8, 2010
ING3 is required for ATM signaling and DNA repair in response to DNA double strand breaks
Audrey Mouche1,2,3, Jérôme Archambeau1,2, Charles Ricordel1,2
1INSERM U1242, Chemistry Oncogenesis Stress and Signaling, CLCC Eugène Marquis, Rennes, France.
Abstract:
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.
Insights
Inhibitor of Growth 3 (ING3) is a tumor suppressor crucial for DNA damage response. Its absence impairs DNA repair and ATM activation, leading to genomic instability.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Inhibitor of Growth 3 (ING3) is a candidate tumor suppressor gene with lost expression in various cancers.
- ING3's role in DNA damage response is not fully understood.
Purpose of the Study:
- To investigate the function of ING3 in DNA damage signaling and repair.
- To determine if ING3 plays a conserved role in response to DNA damage.
Main Methods:
- Depletion of ING3 in human cells and deletion of its yeast ortholog YNG2.
- Assessing sensitivity to DNA damage and ATM activation.
- Analyzing recruitment of DNA damage response proteins (TIP60, NBS1, RNF8, RNF168, 53BP1, BRCA1).
- Evaluating DNA repair pathways (NHEJ, HR) and immunoglobulin class switch recombination (CSR).
Main Results:
- ING3-depleted human cells and YNG2-deleted yeast cells show sensitivity to DNA damage.
- ING3 is recruited to DNA double-strand breaks and is essential for ATM activation.
- ING3 is required for TIP60 recruitment and ATM-mediated phosphorylation of NBS1.
- Absence of ING3 impairs DNA repair (NHEJ, HR) and CSR.
- ING3 is required for the recruitment of RNF8, RNF168, 53BP1, and BRCA1.
Conclusions:
- ING3 functions as a caretaker tumor suppressor by participating in DNA damage signaling and repair.
- ING3's role in DNA double-strand break repair is critical for maintaining genomic stability.
- ING3 is a key mediator in the DNA damage response pathway, regulating ATM activation and downstream repair events.
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