title: c-Myc suppression of DNA double-strand break repair.
abstract: 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.
authors: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors: Zhaozhong
authors: Z
authors: Li
authors: Taofeek K
authors: TK
authors: Owonikoko
authors: Shi-Yong
authors: SY
authors: Sun
authors: Suresh S
authors: SS
authors: Ramalingam
authors: Paul W
authors: PW
authors: Doetsch
authors: Zhi-Qiang
authors: ZQ
authors: Xiao
authors: Fadlo R
authors: FR
authors: Khuri
authors: Walter J
authors: WJ
authors: Curran
authors: Xingming
authors: X
authors: Deng
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism*; D004247:DNA / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005720:Gamma Rays; D055785:Gene Knockdown Techniques; D042822:Genomic Instability / Q000528:radiation effects; D006657:Histones / Q000235:genetics*; D006801:Humans; D000072200:Ku Autoantigen; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D060152:V(D)J Recombination
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen