Cell division transforms mutagenic lesions into deletion-recombinagenic lesions in yeast cells

Mutat Res. 1999 Aug 11;429(1):13-26. doi: 10.1016/s0027-5107(99)00097-4.

Abstract

Cell proliferation has been recognized as an important factor in human and experimental carcinogenesis. Point mutations as well as larger chromosomal rearrangements are involved in the initiation of cancer. In this paper we compared the relative potencies of radiation and chemical carcinogens for inducing point mutations vs. deletions in cell cycle arrested with dividing cells of Saccharomyces cerevisiae. Point mutation substrates and deletion (DEL) recombination substrates were constructed with the genes CDC28 and TUB2 that are required for cell cycle progression through G1 and G2, respectively. The carcinogens ionizing radiation, UV, MMS, EMS and 4-NQO induced point mutations in G1 and in G2 arrested as well as in dividing cells. UV, MMS, EMS and 4-NQO caused very weak if any increases in DEL recombination in G1 or G2 arrested cells, but large increases in dividing cells. When cells treated with carcinogen either in G1 or G2 were allowed to progress through the cell cycle, a time-dependent increase in DEL recombination was seen. Ionizing radiation and the site-specific endonuclease I-SceI, which both directly create double-strand breaks, induced DEL recombination in G1 as well as in G2 arrested cells. In conclusion, UV-, MMS-, EMS- and 4-NQO-induced DNA damage was converted during DNA replication to a lesion capable of inducing DEL recombination which is probably a DNA strand break. Thus, cell proliferation is not necessary to turn DNA alkylation or UV damage into a mutagenic lesion but to convert the damage into a lesion that induces DNA deletions. These results are discussed with respect to mechanisms of carcinogenesis.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Nitroquinoline-1-oxide / adverse effects
  • 4-Nitroquinoline-1-oxide / analogs & derivatives
  • CDC28 Protein Kinase, S cerevisiae / drug effects
  • CDC28 Protein Kinase, S cerevisiae / genetics
  • CDC28 Protein Kinase, S cerevisiae / radiation effects
  • Cell Division / drug effects
  • Cell Division / genetics*
  • Cell Division / radiation effects
  • Chromosome Deletion*
  • DNA, Fungal / drug effects
  • DNA, Fungal / radiation effects
  • Ethyl Methanesulfonate / adverse effects
  • Fungal Proteins / drug effects
  • Fungal Proteins / genetics
  • Fungal Proteins / radiation effects
  • G1 Phase / drug effects
  • G1 Phase / genetics
  • G1 Phase / radiation effects
  • G2 Phase / drug effects
  • G2 Phase / genetics
  • G2 Phase / radiation effects
  • Gamma Rays
  • Methyl Methanesulfonate / adverse effects
  • Mutagenesis
  • Mutagenicity Tests
  • Mutagens / adverse effects
  • Point Mutation / drug effects
  • Point Mutation / radiation effects
  • Quinolones / adverse effects
  • Recombination, Genetic / drug effects
  • Recombination, Genetic / genetics*
  • Recombination, Genetic / radiation effects
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / radiation effects
  • Ultraviolet Rays

Substances

  • 4-nitroquinolone-1-oxide
  • DNA, Fungal
  • Fungal Proteins
  • Mutagens
  • Quinolones
  • 4-Nitroquinoline-1-oxide
  • Ethyl Methanesulfonate
  • Methyl Methanesulfonate
  • CDC28 Protein Kinase, S cerevisiae