O'Hanlon, Karen and Margison, Geoffrey P. and Hatch, Amy and Fitzpatrick, David A. and Owens, Rebecca A. and Doyle, Sean and Jones, Gary W. (2012) Molecular characterization of an adaptive response to alkylating agents in the opportunistic pathogen Aspergillus fumigatus. Nucleic Acids Research, 40 (16). pp. 7806-7820. ISSN 0305-1048

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Abstract

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-N0-nitro-N-nitrosoguanidine (MNNG). We have identified genes that encode MPT and O6-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 O6-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.

Item Type:	Article
Additional Information:	© The Author(s) 2012. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version of this article is available at Nucleic Acids Research (2012) doi:10.1093/nar/gks522
Keywords:	Molecular characterization; adaptive response; alkylating agents; opportunistic pathogen; Aspergillus fumigatus; methylphosphotriester (MPT); DNA repair protein; eukaryotes;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	3779
Identification Number:	https://doi.org/10.1093/nar/gks522
Depositing User:	Dr. Sean Doyle
Date Deposited:	03 Jul 2012 16:01
Journal or Publication Title:	Nucleic Acids Research
Publisher:	Oxford University Press
Refereed:	Yes
URI:	http://nar.oxfordjournals.org/
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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