119: G‑Quadruplex Stabilization Triggers Pericentromeric DNA Breaks in B Cells

️ Episode 119: G‑Quadruplex Stabilization Triggers Pericentromeric DNA Breaks in B Cells In this episode of PaperCast Base by Base, we explore how stabilizing G‑quadruplex DNA structures with small molecules reshapes genome stability in B lymphocytes, revealing fragile hotspots in pericentromeric repeats and ribosomal DNA and exposing checkpoint-dependent differences between primary and malignant cells. Study Highlights:Using the G‑quadruplex stabilizer pyridostatin in mouse primary B cells, a lymphoma line (CH12), and human B cell lines, the authors mapped DNA damage with metaphase spreads and FISH and found recurrent breaks and fusions concentrated at major satellite pericentromeres and rDNA arrays. Primary B cells developed abundant dicentric chromosomes and progressed to tetraploid metaphases, whereas CH12 cells mounted a G2/M checkpoint arrest that limited tetraploid metaphases despite increased tetraploid interphases. Pharmacologic manipulation supported a checkpoint-based mechanism: enforcing G2 arrest with CDK1 inhibition reduced tetraploids and dicentrics, while WEE1 inhibition in CH12 released arrest and increased both. Additional G4 ligands (CX‑5461, Phen‑DC3) also induced pericentromeric instability, reinforcing that G‑quadruplex stabilization is the driver rather than off‑target effects. Conclusion:G‑quadruplex stabilization selectively destabilizes pericentromeric and rDNA repeats in B cells and, by interacting with cell‑cycle checkpoints, may be exploitable to suppress tumor growth while sparing normal cells that respond differently. Reference:Waisertreiger I, Ayele K, Elshaikh MH, Barlow JH. G‑quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in B lymphocytes. Proceedings of the National Academy of Sciences. 2025;122(34):e2506939122. https://doi.org/10.1073/pnas.2506939122 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Keywords: G-quadruplex, pyridostatin, pericentromeric satellite DNA, B lymphocytes, chromosomal instability Chapters (00:00:00) - G4 stabilizing ligands in B cell cancer(00:06:31) - PDS: Targeted DNA damage in cancer(00:08:24) - PDS causes chromosomal instability in cancer cells(00:13:26) - PDS and BRCA2 deficiency cancers(00:17:59) - Base by base science

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