Peer-Reviewed Journal Details
Mandatory Fields
O'Hanlon, KA;Margison, GP;Hatch, A;Fitzpatrick, DA;Owens, RA;Doyle, S;Jones, GW
2012
September
Nucleic Acids Research
Molecular characterization of an adaptive response to alkylating agents in the opportunistic pathogen Aspergillus fumigatus
Published
5 ()
Optional Fields
DNA-REPAIR METHYLTRANSFERASE RESISTANCE GENE PTRA ESCHERICHIA-COLI SACCHAROMYCES-CEREVISIAE METHYLATING AGENTS FUNGAL TREE ADA PROTEIN SEQUENCE NIDULANS DAMAGE
40
7806
7820
An 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.
OXFORD
0305-1048
10.1093/nar/gks522
Grant Details