Translational control of gene expression in yeast and fungal pathogens

Translational control plays an essential role in the regulation of gene expression. It is especially important in defining the proteome, maintaining homeostasis, controlling cell proliferation, growth, and development. Numerous disease states result from aberrant regulation of protein synthesis, therefore understanding the molecular basis and mechanisms of protein translation is critical. The protein synthesis machinery in higher eukaryotic organisms is much more complex than in prokaryotes. Our research is focused on understanding the translational regulatory mechanisms of protein synthesis in yeast and fungal pathogens. Initiation of translation at correct start codon in the mRNA is one of the first events in translation and it determines the reading frame to be decoded. In eukaryotic translation initiation, the 43S pre-initiation complex (PIC), containing initiator Met-tRNA in a ternary complex (TC) with the translation initiation factor 2 (eIF2) bound with GTP, scans the mRNA sequences for start codon in favourable context. However, little is known about the translatome employed by human fungal pathogens during infection.

In last couple of decades the patients with candidiasis has magnified, due to increase in immunocompromised cases that includes individuals suffering from AIDS, patients undergoing solid organ transplantation and chemotherapies. Candida species have high potential to cause life threatening systemic candidiasis in immunocompromised individuals. These pathogens can adapt to host microenvironment and penetrate through deep body tissues during systemic infection. Transcriptional profiling of fungal cells exposed to phagocytes have indicated major influences on ribosome biogenesis and protein synthesis. However the translational regulation that modulates the global translatome and specifically fine tunes the translation of mRNA subgroups for host adaptation or rescue from physiological stress conditions that are encountered during infection, needs to be thoroughly investigated. Our quest is to probe the translation process of pathogenic fungi and identify novel therapeutic targets to treat the fungal diseases in humans.

My lab focus is on two major objectives:

These studies will be performed on Saccharomyces cerevisiae, Candida albicans, Candida glabrata and Candida auris. We will use genetic, genomic, biochemical and molecular biology approaches to address these questions.

• Visiting postdoctoral fellowship at National Institutes of Health – USA, in 2013-2019
• ESF EMBO young scientist travel award in (2011) to attend the conference on “Glutathione and Related Thiols in Living Cells” at Spain.
• Travel award in 2011 from CSIR and DBT India to attend the conference on “Glutathione and Related Thiols in Living Cells” at Spain.
• Awarded Senior Research Fellowship from CSIR India in year 2009-2012.
• Awarded Junior Research Fellowship from CSIR India in year 2007-2009.
• Placed among top 20 percent candidates in National Eligibility Test (NET) for Lectureship by CSIR India, December 2006.
• Qualified GATE (Graduate Aptitude Test for Engineering) in life sciences.
• Awarded best student resident trophy from Govt. College Sector – 11 Chandigarh.

We are looking for enthusiastic candidates who would like to pursue their research career in translation and fungal pathogenesis. We welcome students for short-term training, six-months dissertation, project and PhD. We would be happy to accommodate for Post-Doctoral fellowships such as NPDF, DBT-RA.

1. Anil Thakur^#, Laura Marler^# and Alan G. Hinnebusch (2019) A network of eIF2 interactions with eIF1 and Met-tRNAi promotes accurate start codon selection by the translation preinitiation complex. Nucleic Acid Research, 8;47(5):2574-2593
2. Anil Thakur and Alan G. Hinnebusch (2018) eIF1 Loop 2 interactions with Met-tRNAi control the accuracy of start codon selection by the scanning preinitiation complex. Proc Natl Acad Sci USA, 1;115(18): E4159-E4168.
3. Jinsheng Dong, Colin Echeverría Aitken, Anil Thakur, Byung-Sik Shin, Jon R. Lorsch , and Alan G. Hinnebusch (2017). Rps3/uS3 promotes mRNA binding at the 40S ribosome entry channel and stabilizes preinitiation complexes at start codons. Proc Natl Acad Sci USA, 14;114(11): E2126-E2135
4. Mohaammad Zulkifil, Shambu Yadav, Anil Thakur, Shiffalli Singla, Monika Sharma and Anand K. Bachhawat (2016) Substrate specificity and mapping of residues critical for transport in the high-affinity glutathione transporter Hgt1p. Biochemical Journal, 1;473(15):2369-82.
5. Jose L. Llácer^#, Tanweer Hussain^#, Laura Marler, Colin Echeverría Aitken, Anil Thakur, Jon R. Lorsch, Alan G. Hinnebusch and V. Ramakrishnan (2015) Conformational Differences between Open and Closed States of the Eukaryotic Translation Initiation Complex. Molecular Cell, 6; 59(3): 399–412.
6. Anil Thakur and Anand K. Bachhawat (2015). Charged/Polar-residue scanning of the hydrophobic face of transmembrane domain 9 of the yeast glutathione transporter, hgt1p, reveals a conformationally critical region for substrate transport. Published in G3 (Genes, Genomes, Genetics) Bethesda, 16;5(5):921-9.
7. Anil Thakur and Anand K. Bachhawat (2013). Mutation in the N-terminal region of the Schizosaccharomyces pombe glutathione transporter Pgt1 allows functional expression in Saccharomyces cerevisiae. Yeast, 30(2):45-54.
8. Anand K. Bachhawat, Anil Thakur, Jaspreet Kaur and M.Zulkifli (2013). Glutathione transporters. Biochim Biophys Acta, 1830(5):3154-64.
9. Prashant R Desai^#, Anil Thakur^#, Dwaipayan Ganguli, Sanjoy Paul, Joachim Morschhauser and Anand K. Bachhawat (2011). Glutathione utilization by Candida albicans requires a functional Dug pathway and OPT7, an unusual member of the Oligopeptide transporter family. Journal of Biological Chemistry, 2;286(48):41183-94.
10. Anil Thakur and Anand K. Bachhawat (2010). The role of transmembrane domain 9 in substrate recognition by the fungal high-affinity glutathione transporters. Biochemical Journal, 1;429(3):593-602.
11. Anil Thakur, Jaspreet Kaur and Anand K. Bachhawat (2008). Pgt1, a glutathione transporter from the fission yeast Schizosaccharomyces pombe. FEMS Yeast Research, 8(6):916-29.
(# Equal Contribution)

Book Chapter: