119: G-quadruplexes, pericentromeres, and B cell genome instability

Waisertreiger I et al., PNAS - This study tests how stabilization of G-quadruplex (G4) DNA by ligands such as pyridostatin (PDS) affects genome stability in primary and malignant B cells. The authors map PDS-induced chromosomal breaks and fusions to ribosomal DNA (rDNA) and pericentromeric major satellite (MaSat) repeats and link G4 stabilization to tetraploidization in cells lacking G2/M arrest. Key terms: G-quadruplex, pyridostatin, pericentromeric, ribosomal DNA, tetraploidy. Study Highlights:Pyridostatin (PDS) treatment induces recurrent DNA breaks and chromosome fusions localized mainly to rDNA arrays and pericentromeric MaSat repeats in mouse primary B cells and B cell lymphoma lines. PDS causes high levels of tetraploid metaphases in primary mouse B cells (and in GM12878 cells) that correlate with abundant dicentric chromosomes and absence of a WEE1-dependent G2/M arrest, whereas CH12 cells arrest in G2/M and largely avoid tetraploid metaphases. Similar pericentromeric fragility is seen with the G4 ligand CX-5461 and in human lymphoma cell lines, supporting a role for G4 stabilization in driving pericentromeric instability. Conclusion:G4-stabilizing ligands provoke replication-associated breaks at rDNA and pericentromeric repeats, producing dicentric fusions and, when checkpoint arrest is absent, tetraploidization; this identifies both a vulnerability in B cell cancers and a potential therapeutic avenue with caution for off-target tetraploidization. Music:Enjoy the music based on this article at the end of the episode. Article title:G- quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in B lymphocytes First author:Waisertreiger I Journal:PNAS DOI:10.1073/pnas.2506939122 Reference:Waisertreiger I., Ayelea K., Elshaikha M.H., Barlow J.H. PNAS (2025) doi: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:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/gquadruplex-stabilization-triggers-pericentromeric-dna-breaks-in-b-cells QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-27. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive audit of mechanistic and experimental results: G4 stabilization by PDS, localization of breaks to rDNA and pericentromeric MaSat repeats, tetraploidy in mouse primary B cells and GM12878, absence of tetraploidy in CH12 due to G2/M arrest (and its reversal by inhibitors), human B cell lines (GM12878 and Raji- transcript topics: G-quadruplex structures and PDS mechanism; PDS-induced chromosomal breaks at rDNA and MaSat repeats; tetraploidy and cell-cycle checkpoint differences across cell types; CH12 cells: G2/M arrest, CDK1 inhibition, WEE1 interplay; human B cell lines GM12878 and Raji; PBMC safety; therapeutic implications, drug combinations, and safety considerations QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- PDS stabilizes G-quadruplexes and locks them, hindering hel... 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