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c-Myc suppression of DNA double-strand break repair

Zhaozhong Li1, Taofeek K Owonikoko, Shi-Yong Sun

  • 1Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.

Neoplasia (New York, N.Y.)
|January 12, 2013
PubMed

Insights

c-Myc overexpression impairs DNA double-strand break (DSB) repair by inhibiting the nonhomologous end-joining pathway. This mechanism contributes to genomic instability and tumor development.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Biology

Background:

  • c-Myc is a key regulator of cell growth and proliferation.
  • Overexpression of c-Myc is linked to genetic instability and tumorigenesis.
  • The precise mechanisms by which c-Myc influences DNA repair remain unclear.

Purpose of the Study:

  • To elucidate the mechanism by which c-Myc affects DNA double-strand break (DSB) repair.
  • To investigate the role of c-Myc in V(D)J recombination and genomic instability.
  • To determine how c-Myc interacts with components of the DNA repair machinery.

Main Methods:

  • Utilized a Tet-Off/Tet-On inducible system for conditional c-Myc expression in c-Myc null cells.
  • Assessed DNA double-strand break (DSB) repair, V(D)J recombination fidelity, and chromosomal aberrations.
  • Investigated protein-protein interactions between c-Myc and DNA repair factors (e.g., Ku70, DNA-PKcs) using in vitro and in vivo assays.

Main Results:

  • Conditional c-Myc expression inhibited DNA end-joining and DSB repair, leading to increased chromosomal breaks.
  • c-Myc expression reduced the fidelity of V(D)J recombination.
  • c-Myc directly interacts with Ku70 via its Myc box II domain and disrupts the Ku/DNA-PKcs complex, inhibiting nonhomologous end-joining.

Conclusions:

  • c-Myc suppresses nonhomologous end-joining (NHEJ) pathway activity, thereby inhibiting DSB repair and V(D)J recombination.
  • This inhibition of DNA repair by c-Myc contributes to genomic instability and may drive tumorigenesis.
  • The findings provide critical insights into the oncogenic role of c-Myc through its modulation of DNA repair pathways.

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