The global regulator Ncb2 escapes from the core promoter and impacts transcription in response to drug stress in Candida albicans

Mohd Shariq,Sanjiveeni Dhamgaye,Alok K Mondal,Neha Goyal,Arnab Mukhopadhyay,Remya Nair,Vaibhav Jain,Rajendra Prasad,Gauranga Mukhopadhyay

doi:10.1038/srep46084

Abstract

Ncb2, the β subunit of NC2 complex, a heterodimeric regulator of transcription was earlier shown to be involved in the activated transcription of CDR1 gene in azole resistant isolate (AR) of Candida albicans. This study examines its genome-wide role by profiling Ncb2 occupancy between genetically matched pair of azole sensitive (AS) and AR clinical isolates. A comparison of Ncb2 recruitment between the two isolates displayed that 29 genes had higher promoter occupancy of Ncb2 in the AR isolate. Additionally, a host of genes exhibited exclusive occupancy of Ncb2 at promoters of either AR or AS isolate. The analysis also divulged new actors of multi-drug resistance, whose transcription was activated owing to the differential occupancy of Ncb2. The conditional, sequence-specific positional escape of Ncb2 from the core promoter in AS isolate and its preferential recruitment to the core promoter of certain genes in AR isolates was most noteworthy means of transcription regulation. Together, we show that positional rearrangement of Ncb2 resulting in either activation or repression of gene expression in response to drug-induced stress, represents a novel regulatory mechanism that opens new opportunities for therapeutic intervention to prevent development of drug tolerance in C. albicans cells.

Highlights

CDR1 is a major drug efflux protein-encoding gene which is regulated at the transcriptional as well as at post transcriptional levels[9,16,17,18,19,20,21,22]
We have shown the importance of the β-subunit of Negative Cofactor 2 (NC2) complex in the basal and activated transcription of CDR1 in azole sensitive (AS-Gu4) and azole resistant (AR-Gu5) isolates of C. albicans and provided evidence that this cofactor may be involved in the regulation of select genes, those targeted by Tac[143]
Ncb[2], a part of the heterodimeric NC2 complex that controls transcription of genes was earlier shown to be involved in the activated transcription of CDR1 gene in azole resistant (AR) clinical isolate of C. albicans[43,44]

Summary

Introduction

CDR1 is a major drug efflux protein-encoding gene which is regulated at the transcriptional as well as at post transcriptional levels[9,16,17,18,19,20,21,22]. NC2 is a heterodimer comprised of two subunits, NC2αand NC2β(Ncb2) which was originally recognized as a TATA-binding protein (TBP) activity in human nuclear extracts that repressed RNA Pol II transcription[37,38]. It was later identified in S. cerevisiae as an essential factor and the βand α-subunit-encoding genes are termed as NCB2 (YDR1) and BUR6, respectively[38,39]. We have shown the importance of the β-subunit of NC2 complex in the basal and activated transcription of CDR1 in azole sensitive (AS-Gu4) and azole resistant (AR-Gu5) isolates of C. albicans and provided evidence that this cofactor may be involved in the regulation of select genes, those targeted by Tac[143]. There are hosts of novel MDR genes, which are regulated by Ncb[2] in response to drug stress, leading to transcriptional activation

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Conclusion