121: G-quadruplexes as a Source of Vulnerability in BRCA2-deficient Granule Cell Progenitors and Medulloblastoma

️ Episode 121: G-quadruplexes as a Source of Vulnerability in BRCA2-deficient Granule Cell Progenitors and Medulloblastoma In this episode of PaperCast Base by Base, we explore how DNA secondary structures called G-quadruplexes (G4s) contribute to genome instability and tumor development in BRCA2-deficient cerebellar granule cell progenitors, leading to medulloblastoma. Study Highlights:Using a mouse model with Brca2 deletion in the nervous system and Trp53 loss, researchers observed that these animals developed Sonic Hedgehog (SHH) subgroup medulloblastomas with complete penetrance. Whole-genome sequencing revealed that structural variant breakpoints frequently overlapped with predicted G4-forming sequences, suggesting these structures are key drivers of instability in the absence of BRCA2. Experiments showed that BRCA2-deficient cells had slower replication fork progression when exposed to G4-stabilizing compounds, and upregulation of the G4-resolving helicase PIF1 was identified as a mechanism tumors use to cope with replication stress. Targeting PIF1 in primary tumor cells increased genome instability, highlighting its potential as a therapeutic target. Conclusion:This work establishes G-quadruplexes as a critical source of replication stress in BRCA2-deficient progenitor cells and identifies PIF1 helicase as a promising therapeutic vulnerability in medulloblastoma. Reference:Keahi DL, Sanders MA, Paul MR, Webster ALH, Fang Y, Wiley TF, Shalaby S, Carroll TS, Chandrasekharappa SC, Sandoval-Garcia C, MacMillan ML, Wagner JE, Hatten ME, Smogorzewska A. G-quadruplexes as a source of vulnerability in BRCA2-deficient granule cell progenitors and medulloblastoma. Proc Natl Acad Sci U S A. 2025;122(35):e2503872122. doi:10.1073/pnas.2503872122 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: BRCA2, medulloblastoma, G-quadruplexes, PIF1 helicase, genome instability Chapters (00:00:00) - How DNA defects in children's brains cause cancer(00:02:05) - BRCA2 deficiency in cerebellum cancer(00:07:06) - BRCA2 mutations in brain cancer(00:11:00) - BRCA2 protects the G4(00:12:10) - PIF1 in BRCA2 deficiency medulloblast(00:17:42) - PIF1 and cancer biology

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