Phenotypes of Drosophila homologs of human XPF and XPG to chemically-induced DNA modifications

Abstract

DmXPF ( mei9) and DmXPG ( mus201) mutants are Drosophila homologs of the mammalian XPF and XPG genes, respectively. For Drosophila germ cells, causal correlations exist between the magnitude of a potentiating effect of a deficiency in these functions, measured as the M NER−/ M NER+ mutability ratio, and the type of DNA modification. M NER−/ M NER+ mutability ratios may vary with time interval between DNA adduct formation and repair, mutagen dose and depend also on the genetic endpoint measured. For forward mutations, there is no indication of any differential response of DmXPF compared to DmXPG. Subtle features appeared from a class-by-class comparison: (i) Methylating agents always produce higher M NER−/ M NER+ ratios than their ethylating analogs; (ii) M NER−/ M NER+ mutability ratios are significantly enhanced for cross-linking N-mustards, aziridine and di-epoxide compounds, but not for cross-linking nitrosoureas. The low hypermutability effects with bifunctional nitrogen mustards, aziridine and epoxide compounds are attributed to unrepaired mono-alkyl adducts; (iii) The efficient repair of mono-alkyl-adducts at ring nitrogens in wild-type germ cells is evident from the absence of a dose–response relationship for ethylene oxide, propylene imine and methyl methanesulfonate (MMS). These chemicals become powerful germline mutagens when the NER system is disrupted. Systematic studies of the type performed on germ cells are not available for somatic cells of Drosophila. The sparse data available show large differences in the response of germ cells and somatic cells. The bifunctional agent mechlorethamine (MEC) but not the monofunctional MMS or 2-chloroethylamine cause in NER − XX♀ the highest potentiating effect on mitotic recombination. The causes of the discrepancy between the extraordinarily high activity of MEC in mus201 somatic cells and its low potentiating effect in germ cells is unknown at present.