ArticleMolecular medicine (Cambridge, Mass.)2026
BRIP1, a G-quadruplex DNA helicase, protects against AID-induced genomic instability by limiting R-loop accumulation.
Article in Molecular medicine (Cambridge, Mass.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundBRIP1 (BRCA1-interacting protein 1) or FANCJ is a 5'-3' DNA helicase that plays critical roles in the maintenance of genome stability through its involvement in DNA repair, replication stress responses, and the resolution of DNA secondary structures or non-B DNAs. Defects in the BRIP1 helicase gene are associated with an increased risk of various cancers. It has been shown that BRIP1-deficient mice are predisposed to B-cell lymphoma. Because activation-induced cytidine deaminase (AID)-dependent genomic instability resulting from its mistargeting to non-immunoglobulin genes is a major hallmark of B-cell lymphoma, and non-B DNA structures, including G-quadruplexes (G4) and RNA-DNA hybrids (R-loops), are implicated in AID-induced genomic instability, we asked whether BRIP1 helicase limits these secondary structures to suppress AID-mediated oncogenesis.
methodsWe knocked down (KD) BRIP1 in the CH12F3-2A mouse B-cell, a model cell line for studying AID-induced physiological and non-physiological events and their underlying mechanisms. We also used biophysical assays and in silico tools to study non-B DNAs at human AID off-target sites.
resultsHere, we report that BRIP1 KD increased the frequency of AID-induced events, including IgM-to-IgA antibody switching, somatic hypermutation (SHM), DNA double-strand breaks (DSBs), and IgH/c-Myc chromosomal translocations. However, BRIP1 KD does not affect either the end-joining of AID-induced DNA breaks or the synapsis of switch regions. Importantly, BRIP1 KD resulted in the accumulation of R-loops at both AID targets and off-targets. Furthermore, in silico analysis revealed G4s as the most prevalent form of non-B DNA conformation at AID off-target sites in human. We propose that BRIP1 suppresses AID-induced genomic instability by resolving non-B DNA, thereby potentially limiting the accumulation of genomic lesions that contribute to B-cell lymphoma.
conclusionThese findings revealed that BRIP1 prevents the excessive accumulation of non-B DNAs at AID target sites and suppresses AID-mediated genomic instability. These data also provide a possible explanation for why BRIP1-deficient mice are predisposed to B-cell lymphoma.
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