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Mol Microbiol. 2017 Jan;103(2):347-365. doi: 10.1111/mmi.13562. Epub 2016 Nov 14.

Discovery of McrA, a master regulator of Aspergillus secondary metabolism.

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Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, Kansas, 66045, USA.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California, 90089, USA.
Division of OMICS analysis, Nagoya University Graduate School of Medicine, 65 Tsurumai, Nagoya, Aichi, 466-8550, Japan.
Genome Sequencing and Analysis Program, Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.
Department of Chemistry, Dornsife Colleges of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California, 90089, USA.
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City, Taiwan, 71710, Republic of China.


Fungal secondary metabolites (SMs) are extremely important in medicine and agriculture, but regulation of their biosynthesis is incompletely understood. We have developed a genetic screen in Aspergillus nidulans for negative regulators of fungal SM gene clusters and we have used this screen to isolate mutations that upregulate transcription of the non-ribosomal peptide synthetase gene required for nidulanin A biosynthesis. Several of these mutations are allelic and we have identified the mutant gene by genome sequencing. The gene, which we designate mcrA, is conserved but uncharacterized, and it encodes a putative transcription factor. Metabolite profiles of mcrA deletant, mcrA overexpressing, and parental strains reveal that mcrA regulates at least ten SM gene clusters. Deletion of mcrA stimulates SM production even in strains carrying a deletion of the SM regulator laeA, and deletion of mcrA homologs in Aspergillus terreus and Penicillum canescens alters the secondary metabolite profile of these organisms. Deleting mcrA in a genetic dereplication strain has allowed us to discover two novel compounds as well as an antibiotic not known to be produced by A. nidulans. Deletion of mcrA upregulates transcription of hundreds of genes including many that are involved in secondary metabolism, while downregulating a smaller number of genes.

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