Mechanism of generation and development of chromosomal translocations in human leukemia and lymphoma
Chromosomal translocations are one of the major genomic abnormalities found in different cancers especially in the haematological malignancies, lymphoma and leukemia. My laboratory aims to determine the mechanism of generation of such chromosomal translocations, involving several oncogenes. We study how and why, the DNA breaks at some specific sites in the genome and try to characterize such fragile regions. The steps involved in the progression of such translocation bearing cells into a complete cancerous state are also being investigated.
Role of RAG proteins in genomic instability
The RAG complex (RAG1 and RAG2 proteins), is a sequence specific nuclease involved in generating the immunoglobulin/TCR diversity during V(D)J recombination. RAGs have been shown to cause some chromosomal translocations in T-cell leukemia. We have previously identified a novel property of the RAG complex being a structure specific nuclease as opposed to its classical function. We are in the process of identifying the importance of sequences influencing the RAG cleavage on altered DNA structures, in the context of the human genome. Further mechanistic details of such a property are also being explored. These studies could explain the genomic instability related to lymphoid tissues.
Understanding mechanism of NHEJ in tissues and cancer cells
DNA double strand breaks are the most deleterious damages incurred by the cell. These are primarily repaired by two pathways, homologous recombination (HR) and nonhomologous end joining (NHEJ), of which the latter is predominant in higher eukaryotes. My laboratory works on understanding the mechanism of NHEJ in normal and cancer tissues. Besides, we also study the mechanism of NHEJ in different leukemia and lymphoma, especially due to the high genomic rearrangements present in them. Apart from this, single-strand break repair pathways in different cells are also being investigated.
Screening of synthetic and natural compounds for anti-cancer properties and understanding their mode of action
Another area of research in my laboratory is the screening of various chemically synthesized and naturally derived compounds for anti-cancer properties. We also study their mode of action at the molecular level. The more potent compounds are further tested in vivo in mice models bearing various tumors. Our studies have identified many such promising candidates, some of which are currently investigated in vivo. We also aim to design compounds which are target specific, against proteins which are upregulated specifically in cancers.
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