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G-quadruplexes are a source of vulnerability in BRCA2 deficient granule cell progenitors and medulloblastoma.

Authors :
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
Source :
BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 22. Date of Electronic Publication: 2024 Jul 22.
Publication Year :
2024

Abstract

Biallelic pathogenic variants in the essential DNA repair gene BRCA2 causes Fanconi anemia, complementation group FA-D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under SHH activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four of Brca2 in the central nervous system, coupled with global Trp53 loss. Brca2 <superscript> Δex3-4 </superscript> ;Trp53 <superscript> -/- </superscript> animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping G-quadruplexes (G4s). Brca2 -deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin. Pif1 helicase, which resolves G4s during replication, was highly upregulated in tumors, and Pif1 knockout in primary MB tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment of BRCA2 -deficient medulloblastomas.<br />Competing Interests: Competing Interest Statement A.S. is an advisor to Rocket Pharmaceuticals. Other authors have declared that no conflict of interest exists.

Details

Language :
English
ISSN :
2692-8205
Database :
MEDLINE
Journal :
BioRxiv : the preprint server for biology
Publication Type :
Academic Journal
Accession number :
39091814
Full Text :
https://doi.org/10.1101/2024.07.20.604431