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Critical roles for polymerase zeta in cellular tolerance to nitric oxide-induced DNA damage

Xiaohua Wu1, Katsuya Takenaka, Eiichiro Sonoda

  • 1Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan.

Cancer Research
|January 21, 2006
PubMed

Insights

Nitric oxide (NO) causes DNA damage, particularly chromosomal breaks. Translesion DNA synthesis (TLS) polymerases, like Rev1 and Rev3, are crucial for cells to tolerate this NO-induced genotoxicity.

Area of Science:

  • Molecular Biology
  • Genetics
  • Toxicology

Background:

  • Nitric oxide (NO) is a signaling molecule implicated in inflammation and neuronal regulation.
  • NO's role in mutagenesis is known, but its underlying mechanisms remain unclear.
  • Understanding NO-induced genotoxicity is crucial for cellular protection.

Purpose of the Study:

  • To investigate the mechanisms of NO-induced genotoxicity.
  • To identify DNA repair pathways involved in cellular tolerance to NO.
  • To elucidate the role of translesion DNA synthesis (TLS) in NO-induced DNA damage.

Main Methods:

  • Utilized chicken DT40 cell clones deficient in various DNA repair pathways.
  • Assessed sensitivity to chemical NO donors (spermine NONOate, S-nitroso-N-acetyl-penicillamine).
  • Performed mitotic chromosomal analysis to evaluate DNA breaks.

Main Results:

  • Cells deficient in Rev1 and Rev3 (DNA polymerase zeta subunit) showed hypersensitivity to NO donors.
  • This hypersensitivity correlated with a significant increase in induced chromosomal breaks.
  • TLS polymerases play a critical role in cellular tolerance to NO-induced DNA damage.

Conclusions:

  • Translesion DNA synthesis (TLS) polymerases are essential for repairing NO-induced DNA damage.
  • Error-prone TLS polymerases may contribute to the accumulation of single base substitutions.
  • This study highlights the importance of TLS in mitigating NO genotoxicity.

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