Scholastic record: (https://scholar.google.co.in/citations?user=fef1gNUAAAAJ&hl=en)
Patent filed/granted:
(1) PCT/IN2021/051070
(2) Indian Patent Application No.: 202231013971 (CNA94)
(3) Indian Patent Application No.: 202231043203 (CNA25)
Fellowships and Awards
Genomic Instability and Diseases
Research Summary:
Replication of DNA strands during each cell division is a prerequisite and critical for proper functioning of any genome. It necessitates faithful duplication of the genetic content and ensures genome stability by preventing faulty DNA synthesis that could render spontaneous mutation, genome rearrangement, and DNA breaks. DNA polymerases (Pol) are the enzymes required for DNA synthesis virtually in all the DNA transaction pathways, and any abnormalities in Pol function has been shown to be associated with cell death, tumorigenesis, resistance to chemotherapeutics, and development of an array of complex diseases in humans. In microorganisms, genome instability is also linked to virulence and multidrug resistance. We focus on the mechanism of eukaryotic DNA replication and use both yeasts and human cells as our model systems. Genetic and biochemical studies in S. cerevisiae have indicated that the highly accurate and processive genomic DNA replication is carried out by the coordinated action of Polα-primase, Polδ and Polε (Biochemical Society Trans. 2020 and Current Genetics 2020). PCNA (the eukaryotic clamp loader) is an essential homotrimeric ring protein plays a critical role in orchestrating the assembly of replisome complex, recruiting DNA polymerases, and factors involved in DNA damage response, chromatin assembly and remodeling, and cell cycle control. Each of the PCNA-binding partners harbors a dedicated region called PCNA-interacting protein (PIP) motif. PIPs in all three subunits contribute to processive DNA synthesis by Polδ, and mutational inactivation of all three PIP motifs abrogates its ability to synthesize DNA with PCNA (PNAS, 2011). In human, unlike in yeast, Polδ is a pentameric holoenzyme consisting of p125, p50, p68, and dimeric p12 subunits. An amino-terminal dimerization and a carboxyl terminal PIP motifs in p12 have been mapped, and dimerization of p12 is critical for its interaction with PCNA (LSA, 2019). Although PCNA is a structurally conserved protein, complementation analyses suggest it to be highly species specific (BMC-Micro. 2015 and FEBS letters 2021). By using structural and mutational analyses, we find that the IDCL and J loop structures of PCNA are unique and responsible for cross-species incompatibility, therefore these regions may be targeted to develop species-specific inhibitors (JBC(a)-2021). DNA replication does not proceed smoothly, as it encounters both DNA lesions and non-B form of DNA structures that must be by-passed to prevent collapsing of replication fork. Trans-lesion DNA synthesis (TLS) polymerases are highly sophisticated enzymes can bypass certain lesions in DNA. DNA polymerase eta (Polη) is one such enzymes required for efficient bypass of UV- induced cyclobutane pyrimidine dimers in the genome. Additionally, Polη also possess non-TLS activities such as serum induced morphogenesis, amphotericin B drug resistance and virulence in pathogenic yeast Candida albicans (Molecular Micro.- 2018, Cellular Micro. 2019, and Current Genetics 2019). Further, we identify three distinct group of Polηs from species across kingdom based on their modes of PCNA interaction (JBC (b)-2021). Candida albicans survives as a commensal fungus in the gastrointestinal tract, and its excessive growth causing infections in immune-suppressed individuals is widely accepted. However, our recent data suggests a mutualism between the host and C. albicans. Dietary C. albicans does not cause any noticeable infections, rather it colonizes in the gut to modulate microbiome dynamics which in turn negates the high-fat diet induced uncontrolled body weight gain, metabolic hormonal imbalances, and inflammatory responses. Interestingly, adding C. albicans to a non-obesogenic diet stimulates the appetite regulated hormones and helped the mice gain healthy body weight (biorxiv-2022/M.Spectrum 2022). In its pathogenic state, C. albicans causes fatal systemic infections and are associated with a higher rate of morbidity and mortality, and represent major healthcare problems. Currently, chemotherapy is the sole available option for combating fungal diseases and no vaccine has been developed yet for human use (FCIM-2022). We have generated several genetically engineered knockout strains of C. albicans and also identified few of those strains to be attenuated (Gut microbes-2023). Two of such isolates (CNA94-Indian Patent Application No.: 202231013971 and CNA24- Indian Patent Application No.: 202231043203) have also been patented to explore further as a whole cell vaccine against fungal and other cross-species infections.
Peer reviewed publications:
Satya Ranjan Sahu (UGC-SRF): Mutasome complex and candidiasis
Swagata Bose (ILS-SRF): Polymicrobial interaction and C. albicans pathogenesis
Bhabasha Gyanadeep Utkalaja (UGC-SRF): DNA polymerase epsilon of C. albicans
Jugal Kishore Sahu (CSIR-SRF): Human DNA polymerase theta
Ipsita Subhadarsini (CSIR- SRF): TLS DNA Polymerases and Chemo-resistance
Sushree Subhashree Parida (DBT-JRF): Cell fate without TLS DNA Polymerase
Samanwita Das (CSIR-JRF): t-RNA modification enzymes and fungal pathogenesis
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Sitendra Prasad Panda
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Dr. Kodavati Manohar, Ph. D. (Graduated from the Laboratory in the year 2018) Thesis entitled “Characterization of DNA polymerase eta ( (Polη/Rad30) from pathogenic yeast Candida albicans: Role in genome stability, morphogenesis and multidrug resistance”
( Currently Pursuing Post-doctoral training at Houston Methodist, USA)
Dr. Prashant R. Khandagale, Ph. D. (Graduated from the Laboratory in the year 2019) Thesis entitled “Targeting of human DNA polymerase delta to the replication machinery”.
(Currently Pursuing Post-doctoral training at NIH)
Dr. Premlata Kumari, Ph.D. (Graduated from the Laboratory in the year 2022) Thesis entitled “DNA-protein crosslink repair in pathogenic yeast C. albicans”
(Currently Asst. Prof. Women’s college, Patna)
Dr. Shraddheya Kumar Patel, Ph.D. (Graduated from the Laboratory in the year 2022) Thesis entitled ” Deciphering the role of Pol 32, the non-essential subunit of DNA polymerase delta in Candida albicans pathogenesis”
(Currently Pursuing Post-doctoral training at NIH)
Our Alumni
Manish Singh, Ph.D. (DBT Project RA- 2012 (April-Nov.)
Doureradjou Peroumal, Ph. D. (CISR/DBT-RA- 2016-March 2021)
Amrita Dalei (Lab. Technician – 2013-2018)
Shreenath Nayak, Ph.D. (DBT-RA; from the year 2013-2016)
Jawed Alam, Ph.D. (CSIR-RA)
Avishek Chatterji
Ritayu Chakraborty
Manoj Kumar (IAS Fellow – 2019, Anna University Regional Campus Coimbatore)
Aishi Satpathy (M. Sc. Dissertation-2019, Central University of Tamil Nadu)
Rituparna Moharana (M. Sc. Dissertation-2019, S & O University)
Mousumi Sajjan (Summer project-2018,OUAT, BBSR)
Riya Gupta (IAS Fellow 2017,M. Tech. Biotechnology, Meerut Institute of Engineering and Technology )
Ravi Kumar (IAS Fellow 2016, NIT, Durgapur)
M. Suresh (IAS Fellow 2015)
Aradhana Mishra (M. Sc. Dissertation -2023- Trident. BBSR)
Also see
Best Poster Award (YIM-2023-IISER, Mohali)
narottam74 [at] gmail [dot] com, narottam [underscore] acharya [at] ils [dot] res [dot] in
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Lab. in News
https://vigyanprasar.gov.in/isw/Study-paves-way-for-a-new-approach-to-fight-infections.html
https://thefederal.com/science/indian-researchers-find-new-way-to-fight-infections-with-protein/
We are looking for motivated students (CSIR/DBT/ICMR Fellowship is mandatory) for pursuing Ph.D. in the laboratory.