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DNA repair defects sensitize cells to anticodon nuclease yeast killer toxins

Roland Klassen1, Sabrina Wemhoff, Jens Krause

  • 1Institut für Molekulare Mikrobiologie und Biotechnologie, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany.

Molecular Genetics and Genomics : MGG
|December 29, 2010
PubMed

Insights

Killer toxins disable translation and damage DNA. DNA repair pathways like homologous recombination, base excision repair, and postreplication repair provide resistance to these toxins. Specific tRNA modifications are crucial for toxin activity.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Killer toxins zymocin and PaT inhibit protein synthesis by cleaving specific tRNAs.
  • Anticodon nuclease (ACNase) activity of these toxins also induces DNA damage.
  • Homologous recombination (HR) was previously identified as a protective DNA repair pathway.

Purpose of the Study:

  • To investigate the role of other DNA repair pathways in conferring resistance to ACNase toxins.
  • To elucidate the mechanism by which tRNA cleavage leads to DNA damage and the involvement of tRNA modifications.

Main Methods:

  • Comparative toxin sensitivity analysis of various DNA repair mutants (HR, BER, PRR).
  • Assessment of DNA repair pathway involvement in resistance to zymocin and PaT.
  • Analysis of toxin response in mutants lacking specific tRNA modifications (ELP3/TRM9-dependent wobble uridine modification).

Main Results:

  • Base excision repair (BER) and postreplication repair (PRR) were found to confer resistance to PaT and zymocin, in addition to HR.
  • BER's protective function against ACNase is mediated by endonucleases acting on apurinic (AP) sites, not DNA glycosylases.
  • Mutations in ELP3 or TRM9, affecting tRNA modification, rescued hypersensitivity in DNA repair mutants, indicating DNA damage results from tRNA cleavage.

Conclusions:

  • Multiple DNA repair pathways, including BER and PRR, contribute to cellular resistance against anticodon nuclease toxins.
  • The study highlights a link between translational fidelity, tRNA modification, and genome surveillance mechanisms.
  • Genetic evidence suggests DNA damage is a direct consequence of toxin-induced tRNA cleavage.

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