What is it about?
Our new paper in PNAS explores how stabilizing DNA secondary structures, called G-quadruplexes, affects mouse and human B lymphocytes. DNA is best known for its double-helix shape, but in certain regions it can fold into alternative secondary structures that interfere with the accurate copying or separation of DNA in proliferating cells, particularly in malignant or DNA repair-deficient cells. We discovered that stabilizing G-quadruplexes leads to the accumulation of DNA breaks, which in turn causes chromosomes to fuse together incorrectly. This damage occurred mainly in highly repetitive regions of the genome, including ribosomal DNA and pericentromeric satellite DNA. Importantly, we found that cancerous human B lymphocytes accumulated extensive DNA damage in response to G-quadruplex stabilization, while B lymphocytes from healthy donors did not. Taken together, our findings suggest that G4 stabilization can be a potential therapy for lymphoid cancer treatment.
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Why is it important?
Many cancer treatments preferentially kill tumor cells by causing so much DNA damage the cell dies. But the same treatment can also damage healthy cells causing serious side effects. Finding treatments that specifically damage malignant but not healthy cells is a cornerstone to developing better cancer therapies.
Perspectives
DNA secondary structures have a range of biological functions, but they can also contribute to genetic instability. A particular DNA secondary structure called a G-quadruplex can induce genome instability by creating mutations, deletions, and gross chromosomal rearrangements. Since G-quadruplex structures are present within many human oncogenic promoters and at telomeres, they are promising candidates as a therapeutic target to suppress transcription of oncogenes or to interfere with telomere maintenance in cancer cells. Our findings show that stabilizing G-quadruplex structures leads to chromosomes breaking and fusing in the repetitive regions of the genome. What’s especially important is that cancerous B cells were far more vulnerable to this damage than healthy ones. This raises the possibility of using G-quadruplex stabilization to selectively target cancer cells while sparing normal cells – the biggest need in current cancer therapies. In other words, understanding and regulating G-quadruplex structures could open new horizons in cancer therapy and support a personalized treatment approach in the future.
Dr. Irina Vaysertreyger
University of California Davis
Read the Original
This page is a summary of: G-quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in B lymphocytes, Proceedings of the National Academy of Sciences, August 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2506939122.
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