The Paralogous Genes PDR18 and SNQ2, Encoding Multidrug Resistance ABC Transporters, Derive From a Recent Duplication Event, PDR18 Being Specific to the Saccharomyces Genus

Abstract

Pleiotropic drug resistance (PDR) family of ATP-binding cassette (ABC) transporters play a key role in the simultaneous acquisition of resistance to a wide range of structurally and functionally unrelated cytotoxic compounds in yeasts. Saccharomyces cerevisiae Pdr18 was proposed to transport ergosterol at the plasma membrane, contributing to the maintenance of adequate ergosterol content and decreased levels of stress-induced membrane disorganization and permeabilization under multistress challenge leading to resistance to ethanol, acetic acid and the herbicide 2,4-D, among other compounds. PDR18 is a paralog of SNQ2, first described as a determinant of resistance to the chemical mutagen 4-NQO. The phylogenetic and neighborhood analysis performed in this work to reconstruct the evolutionary history of ScPDR18 gene in Saccharomycetaceae yeasts was focused on the 214 Pdr18/Snq2 homologs from the genomes of 117 strains belonging to 29 yeast species across that family. Results support the idea that a single duplication event occurring in the common ancestor of the Saccharomyces genus yeasts was at the origin of PDR18 and SNQ2, and that by chromosome translocation PDR18 gained a subtelomeric region location in chromosome XIV. The multidrug/multixenobiotic phenotypic profiles of S. cerevisiae pdr18Δ and snq2Δ deletion mutants were compared, as well as the susceptibility profile for Candida glabrata snq2Δ deletion mutant, given that this yeast species has diverged previously to the duplication event on the origin of PDR18 and SNQ2 genes and encode only one Pdr18/Snq2 homolog. Results show a significant overlap between ScSnq2 and CgSnq2 roles in multidrug/multixenobiotic resistance (MDR/MXR) as well as some overlap in azole resistance between ScPdr18 and CgSnq2. The fact that ScSnq2 and ScPdr18 confer resistance to different sets of chemical compounds with little overlapping is consistent with the subfunctionalization and neofunctionalization of these gene copies. The elucidation of the real biological role of ScSNQ2 will enlighten this issue. Remarkably, PDR18 is only found in Saccharomyces genus genomes and is present in almost all the recently available 1,000 deep coverage genomes of natural S. cerevisiae isolates, consistent with the relevant encoded physiological function.

Phylogeny, evolution, and potential ecological relationship of cytochrome CYP52 enzymes in Saccharomycetales yeasts

“…In C. parapsilosis, C. tropicalis, and Y. lipolytica, all of which harbored the greatest number of CYP52 proteins, the extensive expansion of this family could be associated with an evolutionary process for assimilating long chain n-alkanes and fatty acids under several environmental and nutritional conditions. Similar phenomena were observed in other expanded paralogous protein families, including hexose transporters 55 , antifreeze glycoproteins 56 , histones 57 , lipases 58 , and ABC transporters involved in drug resistance 59 , among others. The phenotypic plasticity derived from differential expression of an expanded paralogous family is valuable under changing environmental conditions 60,61 .…”

ABC Transporter Genes Show Upregulated Expression in Drug-Resistant Clinical Isolates of Candida auris: A Genome-Wide Characterization of ATP-Binding Cassette (ABC) Transporter Genes

“…An additional copy of SNQ2 has also been reported in a C. auris isolate belonging to the S. African geographical clade, B11221 (Muñoz et al, 2018). A closer examination suggests that these two Snq2-like proteins form a separate branch from that formed by S. cerevisiae Snq2 and Pdr18, which perform overlapping functions and are considered paralogs (Godinho et al, 2018). The separate blast searches with these two S. cerevisiae proteins show that C. auris CAUR_01276 and CAUR_01285 have 55 and 54% sequence identity with Pdr18 and Snq2, respectively.…”

Crosstalk between Yeast Cell Plasma Membrane Ergosterol Content and Cell Wall Stiffness under Acetic Acid Stress Involving Pdr18

“…An identified player in this process is the plasma membrane ABC transporter Pdr18 [17]. The expression of this pleiotropic drug resistance (PDR) transporter confers resistance to a wide range of chemical and physical stresses, including acetic acid stress [17,[45][46][47][48]. Pdr18 was proposed to mediate ergosterol transport at the plasma membrane, maintaining adequate plasma membrane physical properties under stress induced by acetic acid, which was found to lead to the reduction of ergosterol content [17].…”