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Bcl2 suppresses DNA repair by enhancing c-Myc transcriptional activity

Zhaohui Jin1, W Stratford May, Fengqin Gao

  • 1University of Florida Shands Cancer Center, Department of Medicine, Gainesville, Florida 32610-0232, USA.

The Journal of Biological Chemistry
|March 24, 2006
PubMed

Insights

Bcl2 protein suppresses DNA repair of cigarette smoke-induced damage by interacting with c-Myc. This interaction inhibits apurinic/apyrimidinic endonuclease 1 (APE1), promoting DNA damage accumulation and potentially leading to cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • DNA Repair Mechanisms

Background:

  • Bcl2 and c-Myc are oncogenic proteins implicated in DNA damage and tumorigenesis.
  • The precise mechanisms by which these proteins contribute to cancer development remain unclear.
  • Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) from cigarette smoke is a potent carcinogen causing DNA damage.

Purpose of the Study:

  • To elucidate the mechanism by which Bcl2 influences DNA repair, particularly in the context of NNK-induced damage.
  • To investigate the role of c-Myc in Bcl2-mediated suppression of DNA repair.
  • To identify downstream targets involved in the Bcl2/c-Myc pathway affecting DNA repair.

Main Methods:

  • Investigated the interaction between Bcl2 and c-Myc using domain mapping (Bcl2 BH4 and c-Myc MBII domains).
  • Assessed the effect of Bcl2 and c-Myc on the repair of NNK-induced DNA lesions, specifically abasic sites.
  • Examined the subcellular localization of Bcl2 and c-Myc, including nuclear expression.
  • Studied the impact of c-Myc depletion on DNA repair in Bcl2-overexpressing cells.
  • Analyzed the expression levels of apurinic/apyrimidinic endonuclease 1 (APE1) in relation to Bcl2 and c-Myc.

Main Results:

  • Bcl2 suppresses the repair of NNK-induced DNA abasic sites, correlating with increased c-Myc transcriptional activity.
  • The Bcl2 BH4 domain directly binds to the c-Myc MBII domain, mediating enhanced c-Myc activity and DNA repair inhibition.
  • Nuclear Bcl2 co-localizes with c-Myc, enhancing c-Myc activity and suppressing DNA repair, but not cell survival.
  • Depletion of c-Myc accelerates NNK-induced DNA damage repair in Bcl2-overexpressing cells, highlighting c-Myc's essential role.
  • Overexpression of Bcl2 leads to c-Myc up-regulation and APE1 down-regulation, suggesting APE1 is a downstream target.

Conclusions:

  • Bcl2 employs a novel mechanism, involving c-Myc and APE1, to suppress DNA repair, independent of its survival function.
  • This Bcl2-mediated suppression of DNA repair contributes to DNA damage accumulation, genetic instability, and tumorigenesis.
  • Targeting the Bcl2/c-Myc/APE1 pathway may offer new therapeutic strategies for cancers associated with cigarette smoke exposure.

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