What does this research mean for the field?

G4 DNA structures at the BCL6 Cluster III region contribute to chromosomal fragility and translocation in diffuse large B-cell lymphoma (DLBCL). Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study aims to explore how G4 DNA structures in the BCL6 gene contribute to chromosomal translocations in DLBCL.

March 12, 2026Journal of Biological Chemistry0 citationsOpen Access

Canonical and Noncanonical Forms of G4 DNA at the Cluster III of BCL6 Breakpoint Region Could Lead to Chromosomal Translocation in DLBCL

SJSaniya M. JavadekarIndian Institute of Science Bangalore SDSayak DasAssam University SHSujatha M. HanumegowdaIndian Institute of Science Bangalore

Key Points

This study aims to explore how G4 DNA structures in the BCL6 gene contribute to chromosomal translocations in DLBCL.
In silico analyses to identify G4 formation at BCL6 Cluster III.
Gel shift assays and circular dichroism to confirm G4 folding.
Mutation studies to examine G4 conformations using various G-stretches.
Sodium bisulfite modification assays to detect single-stranded regions.
Ex vivo assays to assess the impact of G4 structures on transcription.
Confirmation of G4 formation at BCL6 Cluster III through multiple assays.
Discovery of various G4 conformations that could lead to replication stalling.
Identification of fragile hotspots within Cluster III linked to G4 structures.
Demonstration that G4 structures impede transcription, contributing to chromosomal instability.

Abstract

Cancer arises from the accumulation of genetic alterations, including chromosomal translocations and deletions.Faulty repair of DNA double-strand breaks can give rise to such chromosomal rearrangements.In this study, we focus on diverse translocations that share a common partner, BCL6 on chromosome 3, which are implicated in diffuse large B-cell lymphoma (DLBCL).Analysis of patient breakpoints identified several breakpoint clusters within BCL6, of which Cluster III is the focus of this work.Here, we investigate the role of non-B DNA structures in imparting chromosomal fragility.In silico analyses, gel shift assays, and circular dichroism confirmed G-quadruplex (G4) formation at BCL6 Cluster III.Mutation studies revealed multiple G4 conformations utilizing distinct G-stretches, including GNG motifs.Disrupting G4forming sequences in this region enhanced plasmid propagation in E. coli, indicating structuredependent replication stalling.Sodium bisulfite modification assays detected single-stranded character here, both in plasmids and chromosomal DNA, suggesting additional fragility hotspots within Cluster III.Ex vivo assays showed that the G4 structure blocks transcription as a roadblock.Together, these data demonstrate that G4 folding in BCL6 Cluster III generates partially single-stranded regions, rendering the locus prone to breakage and translocation.

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