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Maintenance of Genome Integrity- the shield against cancer

Recent work from Dr. Sagar Sengupta’s (National Institute of Immunology, New Delhi) laboratory published in Nature Communications has demonstrated that BLM helicase, the protein mutated in Bloom Syndrome, has an important role in the maintenance of the integrity of the human genome by acting at multiple steps in the DNA damage recognition and repair pathways. In this publication the authors have used an unique system by which they could introduce damage at specific locations in the human genome. This experimental design has allowed them to determine how BLM localizes to the damage sites, its kinetics of accumulation at these sites, whether BLM recruitment depends on other factors in the response pathway and finally delineates how the cell decides which repair pathway it should use to eliminate the lesion. Hence this work gives a frame work to design therapeutic interventions to artificially accelerate the process by which the integrity of the genome can be sustained. A schematic diagram which summerizes the finding in this publication is presented in Figure 1A.

Figure 1: (A) Mechanism of BLM recruitment to the DSBs and its effect on DNA repair. (B) Schematic diagram showing the mechanism by which BLM regulates c-Jun turnover and thereby its functions in vivo.


Since patients with mutant BLM are predisposed to cancer, BLM can be considered as a caretaker of the genome having global effects to maintain the genome stability. One way by which such a tumour suppressor can maintain genomic integrity and prevent the development of cancer is by directly or indirectly nullifying the functions of a class of proteins which promote the development of cancer, namely the oncogenes. In another recent paper published from Dr. Sengupta’s group in Cell Reports it has been demonstrated how the BLM helicase helps in the enhanced degradation of a key oncogene, c-Jun in colon cancer cells. BLM acts like a clamp causing better interaction between the oncogene (i.e. c-Jun) and the protein which normally degrades it, namely Fbw7 (member of a class of protein called E3 ligase). Further BLM can reactivate defective Fbw7 which is mutated in approximately 20% colon cancer patients and help it to bind to c-Jun. Since c-Jun is a potent regulator of a huge cascade of genes required for tumour promotion, decreased c-Jun levels leads to its compromised function which culminates in lesser tumour load in mouse xenograft models. Hence this work leads to a discovery of a potential therapeutic intervention for a significant fraction of colon cancer patients whereby overexpression of BLM in cells expressing mutant Fbw7 should lead to tumour remission. A schematic diagram which summerizes the finding in this publication is presented in Figure 1B.

Dr. Sengupta’s work has been funded as an Unit of Excellence by Department of Biotechnology, Government of India.