c-Myc Suppression of DNA Double-strand Break Repair

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2012-12, Vol.14 (12), p.1190-IN35
• Main Authors: Li, Zhaozhong, Owonikoko, Taofeek K, Sun, Shi-Yong, Ramalingam, Suresh S, Doetsch, Paul W, Xiao, Zhi-Qiang, Khuri, Fadlo R, Curran, Walter J, Deng, Xingming
• Format: Article
• Language: English
• Subjects: Antigens, Nuclear - metabolism; Apoptosis; c-Myc protein; Catalytic subunits; Chromatids; DNA; DNA - radiation effects; DNA Breaks, Double-Stranded; DNA damage; DNA End-Joining Repair; DNA repair; DNA-Activated Protein Kinase - metabolism; DNA-Binding Proteins - metabolism; DNA-dependent protein kinase; Double-strand break repair; Fidelity; gamma Radiation; Gamma Rays; Gene Knockdown Techniques; Genomic instability; Genomic Instability - radiation effects; Histones - genetics; Humans; Ku Autoantigen; Ku70 protein; Mutation; Myc protein; Nuclear Proteins - metabolism; Null cells; Oncology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA Interference; Tumorigenesis; V(D)J Recombination
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.121258

c-Myc is a transcriptional factor that functions as a central regulator of cell growth, proliferation, and apoptosis. Overexpression of c-Myc also enhances DNA double-strand breaks (DSBs), genetic instability, and tumorigenesis. However, the mechanism(s) involved remains elusive. Here, we discovered that γ-ray ionizing radiation-induced DSBs promote c-Myc to form foci and to co-localize with γ-H2AX. Conditional expression of c-Myc in HO15.19 c-Myc null cells using the Tet-Off/Tet-On inducible system results in down-regulation of Ku DNA binding and suppressed activities of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and DNA end-joining, leading to inhibition of DSB repair and enhanced chromosomal and chromatid breaks. Expression of c-Myc reduces both signal and coding joins with decreased fidelity during V(D)J recombination. Mechanistically, c-Myc directly interacts with Ku70 protein through its Myc box II (MBII) domain. Removal of the MBII domain from c-Myc abrogates its inhibitory effects on Ku DNA binding, DNA-PKcs, and DNA end-joining activities, which results in loss of c-Myc's ability to block DSB repair and V(D)J recombination. Interestingly, c-Myc directly disrupts the Ku/DNA-PKcs complex in vitro and in vivo . Thus, c-Myc suppression of DSB repair and V(D)J recombination may occur through inhibition of the nonhomologous end-joining pathway, which provides insight into the mechanism of c-Myc in the development of tumors through promotion of genomic instability.