Author interview: Ritu Agrawal is a Research Associate at NIBMG, Kalyani, under Dr. Sagar Sengupta, specializing in molecular and cellular biology with a focus on DNA damage. She earned her PhD from NII, New Delhi.
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Lab: Dr. Sagar Sengupta, BRIC-National Institute of Biomedical Genomics, Kalyani, India, BRIC-National Institute of Immunology, New Delhi, India
The 20-mer phosphomimetic BLM peptide enhances ATM activation and DDR, restoring DNA repair even without irradiation, highlighting its potential as a therapeutic DDR agonist to prevent neoplastic transformation.
What was the core problem you aimed to solve with this research?
While ATM kinase plays a crucial role in responding to double-strand breaks (DSBs), most studies have focused on ATM inhibitors to chemosensitize cancer cells. However, to date, not a single ATM inhibitor has successfully progressed beyond Phase I clinical trials. We aimed to test the adage “prevention is better than cure” in the context of cancer biology. We hypothesised that by enhancing the DNA damage response (DDR), cancer initiation could be delayed or even prevented. Therefore, we sought to identify DDR agonists capable of restoring DDR activation and improving genomic integrity.
Enhancing the DNA damage response to repair harmful mutations before they take effect could delay cancer onset in susceptible populations. This study represents a potential paradigm shift in cancer prevention and management. — Dr. Sagar Sengupta
How did you go about solving this problem?
Our previous study (published in Nature Communications) revealed that BLM recruitment to DNA damage sites depends on ATM activity. In this study, we explored whether BLM also plays a role in ATM activation and whether a critical feed-forward loop exists between BLM and ATM. We checked ATM activation in presence and absence of BLM to assess the impact of BLM on the DNA damage response. To pinpoint the specific region of BLM responsible for enhancing ATM activation, we fragmented the BLM protein and tested each segment’s effect on ATM activity. Finally, we reintroduced the 20-mer BLM peptide into BLM knockout mice to determine its potential to restore ATM activation and DNA damage response.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Our research outcomes suggest a potential breakthrough in cancer prevention.
- How Our Cells Repair DNA:
Our bodies have natural repair mechanisms to fix damaged DNA, preventing harmful mutations that can lead to cancer. A key player in this process is an ATM protein, which gets activated when DNA is damaged. - Role of BLM in DNA Repair:
This study found that BLM plays a crucial role in boosting ATM activation, which is essential for repairing damaged DNA. When BLM is missing or not working properly, ATM cannot activate effectively, weakening the cell’s ability to fix DNA damage. This failure in DNA repair increases the risk of harmful mutations and cancer development. - Small BLM Peptide Boosts Repair:
We discover a 20-mer peptide of BLM that can restore ATM activity. This peptide helps in activating ATM even when DNA damage isn’t directly triggered, making the repair system stronger. - Why This Matters for Cancer Prevention:
By enhancing DNA repair, this peptide could prevent cancer from forming in the first place, especially in people with genetic defects that weaken their DNA repair systems. It could also help make existing cancer treatments more effective.
What are the potential implications of your findings for the field and society?
The 20mer phosphomimetic BLM peptide may act as a key barrier to neoplastic transformation by boosting or reactivating the DNA damage response in both the cellular environment and precancerous tissues. This could lead to the delay or even prevention of cancer initiation and progression, offering new avenues for cancer prevention and therapeutic strategies, ultimately improving public health outcomes.
What was the exciting moment during your research?
The most exciting moment in my research was observing a strong ATM activation in BLM wild-type mice upon irradiation, while no such activation occurred in BLM knockout mice. Another thrilling discovery was when the 20-mer BLM peptide demonstrated the ability to activate ATM. Remarkably, introducing the BLM peptide T99E (91–110 aa) into BLM knockout mice restored ATM activation to wild-type levels, even without irradiation—an absolutely mesmerizing finding.
Reference: Agrawal, R., Agarwal, H., Mukherjee, C., Chakraborty, B., Sharma, V., Tripathi, V., Kumar, N., Priya, S., Gupta, N., Jhingan, G. D., Bajaj, A., & Sengupta, S. (2025). Phosphorylated BLM peptide acts as an agonist for DNA damage response. Nucleic acids research, 53(4), gkaf106. https://doi.org/10.1093/nar/gkaf106
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