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Human tumor cell strains defective in the repair of alkylation damage

R S Day1, C H Ziolkowski, D A Scudiero

  • 1Nucleic Acids Section, Laboratory of Molecular Carcinogenesis, CIP, DCCP, NCI, NIH, 9000 Rockville Pike, Bethesda, MD 20034, USA.

Carcinogenesis
|January 31, 2012
PubMed

Insights

Human tumor cells defective in repairing N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) DNA damage exhibit increased sensitivity to MNNG. This DNA repair deficiency, termed the Mer(-) phenotype, is found in various human tumors.

Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • Human astrocytoma cell strains were previously found to be defective in repairing N-methyl-N itro-N-nitrosoguanidine (MNNG) damaged adenovirus 5.
  • DNA repair mechanisms are crucial for maintaining genomic integrity and preventing cellular transformation.

Purpose of the Study:

  • To investigate the sensitivity of MNNG-damaged DNA repair-deficient human tumor cell strains to MNNG.
  • To characterize the prevalence and nature of the DNA repair deficiency phenotype in human tumors.

Main Methods:

  • Assessing colony-forming ability of tumor cell strains after MNNG exposure.
  • Evaluating DNA synthesis inhibition and repair synthesis following MNNG treatment.
  • Testing sensitivity to DNA damage induced by various N-alkylating agents.

Main Results:

  • Two MNNG repair-deficient astrocytoma cell strains showed high sensitivity to MNNG-induced cell killing, unlike normal fibroblasts or other tumor strains.
  • The Mer(-) phenotype, characterized by deficient repair of MNNG-damaged adenovirus 5, was identified in 9 out of 39 human tumor strains.
  • Mer(-) cells exhibited persistent inhibition of semi-conservative DNA synthesis post-MNNG treatment and paradoxically higher MNNG-stimulated repair synthesis compared to Mer(+) cells.
  • Mer(-) cells demonstrated impaired repair of viruses damaged by various N-alkylating agents.

Conclusions:

  • A subgroup of human tumor cells (Mer(-)) displays a specific deficiency in repairing DNA damage induced by MNNG and related compounds.
  • This DNA repair defect correlates with increased sensitivity to MNNG and affects DNA synthesis recovery.
  • The Mer(-) phenotype is present in diverse human tumor types and represents a potential target for cancer therapy.

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