We are interested to understand how the macromolecular machinery performing replication (i.e. the “replisome”) functions. While we know quite a bit about how the individual protein components of the replisome work, how these proteins come together and catalyze replication as a whole is less clear.  On the other hand, these macromolecular interactions are essential for modulating different aspects of replication such that genome duplication can occur in co-ordination with other cellular processes.

We are currently focusing our efforts to understand the molecular mechanism of replication in the organelle called “apicoplast”. Apicoplasts are non-photosynthetic plastids essential for the survival of pathogenic eukaryotes such as Plasmodium and Toxoplasma, causative agents of infectious diseases like malaria and toxoplasmosis. The apicoplast replicates and maintains its own organellar genome by recruiting and assembling a specialized replication machinery for this sole purpose. The essential nature of this organelle in the context of a pathogen presents apicoplast replication as a potential target for drug development that could help address growing concerns over the emergence drug-resistant pathogenic strains worldwide. However, at present we know very little about how this molecular machine works. Using transient state enzyme kinetics, next-generation DNA sequencing and single particle cryo-electron microscopy we are trying to decipher the molecular mechanism of action of the apicoplast replisome and its implications in the larger context of pathogenesis.

 

Please check out the lahiri lab website for more information.

Wellcome Trust/DBT India Alliance Intermediate Fellowship (year of award: 2020)

1. Deniston CA*, Salogiannis J*, Mathea S*, Snead D, Lahiri I, Donosa O, Watanabe R, Bohning J, Shiau A, Knapp S, Villa E, Reck-Peterson SL, Leschziner AE. (2020) Parkinson’s Disease-linked LRRK2 structure and model for microtubule interaction. Nature. (https://doi.org/10.1038/s41586-020-2673-2).
2. Lahiri I, Xu J, Han BG*, Oh J*, Wang D, DiMaio F, Leschziner AE. (2019) 3.1Å structure of yeast RNA polymerase II elongation complex stalled at a cyclobutane pyrimidine dimer lesion solved using streptavidin affinity grids. J Struct Biol. 207(3):270-78.
3. Cianfrocco MA, Lahiri I, DiMaio F, Leschziner AE. (2018) cryoem-cloud-tools: A software platform to deploy and manage cryo-EM jobs in the cloud. J Struct Biol. 203(3):230-35.
4. Xu J*, Lahiri I*, Wang W, Wier A, Cianfrocco MA, Chong J, Hare A, Dervan PB, DiMaio F, Leschziner AE, Wang D. (2017) Structural Basis for Eukaryotic Transcription-Coupled DNA Repair Initiation. Nature. 551(7682):653-57.
5. Mukherjee P*, Wilson RC*, Lahiri I, Pata JD. (2014) Three residues of the interdomain linker determine the conformation and single-base deletion fidelity of Y-family translesion polymerases. J Biol Chem. 289(10):6323
6. Lahiri I*, Mukherjee P*, Pata JD. (2013) Kinetic Characterization of Exonuclease-Deficient Staphylococcus aureus PolC, a C-family Replicative DNA Polymerase. PLoS ONE. 8(5): e63489.
7. Mukherjee P*, Lahiri I*, Pata JD. (2013) Human polymerase kappa uses a template-slippage deletion mechanism, but can realign the slipped strands to favour base substitution mutations over deletions. Nucleic Acids Res. 41(9):5024-35.           

* Equal contribution author.

Please check out the lahiri lab website for more information.