Year: 2026
Type: preprint
Abstract: How fibrillarin (FBL), an RNA 2′-O-methyltransferase, regulates antibody diversification remains unclear. This study demonstrated that FBL promotes switch (S)–S DNA synapsis at the IgH locus during class switch recombination (CSR), without affecting DNA cleavage. Both RNA-binding and catalytic activities of FBL were essential for CSR. Moreover, MED19 supported DNA cleavage and synapsis by regulating snoRNAs that guide 2′-O-methylation. Mechanistically, FBL methylated α-germline transcripts (α-GLTs), cis-acting noncoding RNAs forming nuclear condensates harboring machinery for RNA processing, RNP remodeling, and chromatin dynamics. FBL-mediated 2′-O-methylation governed condensate protein composition. FBL suppression aberrantly enriched nucleolar proteins, including WDR74. Crucially, low WDR74 expression in B cells promoted μ- and α-GLT condensate fusion, thereby enhancing S–S synapsis, CSR, and IgH/c-Myc translocation, potentially contributing to poor myeloma prognosis. Altogether, our findings revealed that RNA 2′-O-methylation dictates GLT condensate composition and fusion dynamics to establish a recombination center, driving genomic DNA synapsis in B cells.
Institutions: Kyoto University, Center for Cancer Immunotherapy and Immunobiology, Kyoto University, Hirosaki University, Shizuoka University, Research Institute of Green Science and Technology, Shizuoka University, Kindai University, Institute of Advanced Medical Sciences, Tokushima University, Institute of Photonics and Human Health Frontier, Tokushima University, Tokushima University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225404423