Biography

Research Projects

Molecular Mechanism of transcription activation of genes repressed by NFkappaB: 

The Nuclear Factor kappaB (NF−κB) family of induced transcription factor proteins plays a vital role in the immune response of higher organisms. Though NF−κB is a well-known transcription activator it also functions as a transcription repressor for many genes. The mechanism of transcription activation of such NF−κB-repressed genes remains poorly understood, which we intend to address through this proposal. 

We hypothesize that ‘subtle changes in specific NF−κB dimer stability on κB-DNA site of the promoter/enhancer region of NF−κB-repressed genes decide their transcriptional outcome’. 
Here my lab is working ‘to study the mechanism of transcription activation of NF−κB-repressed Interferon Regulatory factor (IRF) target genes. The research outcome will provide insights for engineering ways to regulate the transcription of specific genes that get deregulated in diseased cells.

Understanding NF-kappaB dimer dynamics in NF-kappaB driven transcription : 

NF-kappaB (NF−κΒ) refers to a family of proteins, which regulate the expression of a large number of genes important for human health. In normal cells, NF−κΒ activity is regulated. Activated NF−κΒ migrates to the nucleus and binds to its DNA recognition sites and regulates its target gene transcription. Abnormally high NF−κΒ activity has been recognized as a critical factor in cancer and inflammatory diseases. 

This makes NF−κΒ an important drug target in the malignant cells. The NF−κΒ family is comprised of five members, namely, p50, p52, RelA, RelB and c-rel. The family members form dimers in various combinations amongst themselves with RelA:p50 heterodimer being the most abundant followed by p50 homodimer; the other dimers either exist at very low concentrations physiologically and in some cases are not observed experimentally. 

The sequence of the κB DNA on the promoter/enhancer site of a target gene plays a major role in the preferential binding of certain NF−κB dimers. 
My lab is working towards understanding the formation and stabilization of different NF−κΒ dimers using various biophysical and molecular biology techniques.

Understanding Gene Regulation and Targeting protein-protein Interactions in a proto-oncogene System:

Bcl3 (B cell lymphoma 3) protein has an emerging role in a number of autoimmune pathologies and different cancers. It is identified as a proto-oncogene with a central role in regulating NF-kappaB signaling. Belonging to the IkappaB family of proteins, which is known for its inhibitory role of the NF-kappaB pathway, Bcl3 plays a dual role in transcription activation as well as repression of NF-kappaB target genes. 

It accomplishes its role as a transcription regulator by interacting with p50 and p52 subunits of NF-kappaB in their homodimer form. Though the interaction of Bcl3 with p50 and p52 homodimers is well-established the details of the interaction active site of the proteins required for designing any potential drug target remains elusive. This is despite the fact that 3-dimensional crystal structures of the individual components of the Bcl3-p50/p52 complex, namely, Bcl3, p50 homodimer, and p52 homodimer are now available for over a decade. 
My lab is working to study this interaction using various biophysical techniques.

Key Publications

1. Kumar M et al Domain Stability Regulated through the Dimer Interface Controls the Formation Kinetics of a Specific NF-κB Dimer. (2021) Biochemistry. 60:513-523. *

2. Raza T et al Insights into the NF-κB-DNA Interaction through NMR Spectroscopy. (2021) ACS Omega. 6:12877-12886. * 

3. Mukherjee SP et al. Structural characterization of the ternary complex that mediates termination of NF-κB signaling by IκBα. (2016) Proc Natl Acad Sci USA 113:6212-7. 

4. Mukherjee SP et al NMR characterization of a 72 kDa transcription factor using differential isotopic labeling. (2016) Protein Sci 25:597-604

5. Mukherjee SP et al. Structural analysis of the RelA: CBP/p300 interaction reveals its functional role in RelA-driven transcription. (2013) Plos Biol 11(9).