Molecular characterization of an adaptive response to alkylating agents in the opportunistic pathogen Aspergillus fumigatus.
AffiliationBiotechnology Laboratory, Department of Biology, National University of Ireland, Maynooth, County Kildare, Ireland
MetadataShow full item record
AbstractAn adaptive response to alkylating agents based upon the conformational change of a methylphosphotriester (MPT) DNA repair protein to a transcriptional activator has been demonstrated in a number of bacterial species, but this mechanism appears largely absent from eukaryotes. Here, we demonstrate that the human pathogen Aspergillus fumigatus elicits an adaptive response to sub-lethal doses of the mono-functional alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We have identified genes that encode MPT and O(6)-alkylguanine DNA alkyltransferase (AGT) DNA repair proteins; deletions of either of these genes abolish the adaptive response and sensitize the organism to MNNG. In vitro DNA repair assays confirm the ability of MPT and AGT to repair methylphosphotriester and O(6)-methylguanine lesions respectively. In eukaryotes, the MPT protein is confined to a select group of fungal species, some of which are major mammalian and plant pathogens. The evolutionary origin of the adaptive response is bacterial and rooted within the Firmicutes phylum. Inter-kingdom horizontal gene transfer between Firmicutes and Ascomycete ancestors introduced the adaptive response into the Fungal kingdom. Our data constitute the first detailed characterization of the molecular mechanism of the adaptive response in a lower eukaryote and has applications for development of novel fungal therapeutics targeting this DNA repair system.
CitationMolecular characterization of an adaptive response to alkylating agents in the opportunistic pathogen Aspergillus fumigatus. 2012, 40 (16):7806-20 Nucleic Acids Res
JournalNucleic Acids Research
- Comparative analysis of O6-methylguanine methyltransferase activity and cellular sensitivity to alkylating agents in cell strains derived from a variety of animal species.
- Authors: Ikenaga M, Tsujimura T, Chang HR, Fujio C, Zhang YP, Ishizaki K, Kataoka H, Shima A
- Issue date: 1987 Sep
- Induction of c-fos, c-jun, junB and junD mRNA and AP-1 by alkylating mutagens in cells deficient and proficient for the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) and its relationship to cell death, mutation induction and chromosomal instability.
- Authors: Dosch J, Kaina B
- Issue date: 1996 Nov 7
- The contribution of O6-methylguanine and methylphosphotriesters to the cytotoxicity of alkylating agents in mammalian cells.
- Authors: Hall J, Kataoka H, Stephenson C, Karran P
- Issue date: 1988 Sep
- Relationship between O6-alkylguanine-DNA alkyltransferase activity and N-methyl-N'-nitro-N-nitrosoguanidine-induced mutation, transformation, and cytotoxicity in C3H/10T1/2 cells expressing exogenous alkyltransferase genes.
- Authors: von Hofe E, Fairbairn L, Margison GP
- Issue date: 1992 Dec 1
- Expression of the inactive C145A mutant human O6-alkylguanine-DNA alkyltransferase in E.coli increases cell killing and mutations by N-methyl-N'-nitro-N-nitrosoguanidine.
- Authors: Edara S, Kanugula S, Pegg AE
- Issue date: 1999 Jan