G-quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in B lymphocytes

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• DNA secondary G-quadruplex (G4) structures can impede DNA replication.
• Replication stress due to G4 processing defects is linked to B cell cancers and premalignant cells.
• Genome instability and chromosome rearrangements are hallmarks of cancer, particularly B cell malignancies.

Purpose of the Study:

• To investigate the impact of G4-stabilizing ligands on genome instability in primary and malignant B cells.
• To assess the differential response of primary versus malignant B cells to G4 stabilization.

Main Methods:

• Treatment of mouse primary B cells and CH12 lymphoma cells with pyridostatin (PDS).
• Analysis of DNA damage, chromosome breaks, and rearrangements in treated cells.
• Evaluation of cell cycle progression (G2/M arrest) and ploidy changes (tetraploidy).

Main Results:

• Pyridostatin induced DNA breaks and rearrangements in ribosomal DNA and pericentromeric regions in both primary and malignant B cells.
• Primary B cells exhibited high levels of tetraploid metaphase cells and dicentric chromosomes after PDS treatment.
• Malignant CH12 cells activated G2/M checkpoints, preventing tetraploidy and extensive damage seen in primary cells.

Conclusions:

• Primary and malignant B cells exhibit distinct responses to G4-stabilizing compounds.
• Pyridostatin causes significant genome instability, with malignant B cells showing a more robust checkpoint-mediated resistance.
• G4-stabilizing drugs hold therapeutic promise for selectively targeting B cell tumor growth by exploiting differential cellular responses.