Immunoglobulin heavy chain (IgH) locus-associated G-rich long noncoding RNA (SμGLT) is important for physiological and pathological B cell DNA recombination. We demonstrate that the METTL3 enzyme-catalyzed N⁶-methyladenosine (m⁶A) RNA modification drives recognition and 3′ end processing of SμGLT by the RNA exosome, promoting class switch recombination (CSR) and suppressing chromosomal translocations. The recognition is driven by interaction of the MPP6 adaptor protein with nuclear m⁶A reader YTHDC1. MPP6 and YTHDC1 promote CSR by recruiting AID and the RNA exosome to actively transcribe SμGLT. Direct suppression of m⁶A modification of SμGLT or of m⁶A reader YTHDC1 reduces CSR. Moreover, METTL3, an essential gene for B cell development in the bone marrow and germinal center, suppresses IgH-associated aberrant DNA breaks and prevents genomic instability. Taken together, we propose coordinated and central roles for MPP6, m⁶A modification, and m⁶A reader proteins in controlling long noncoding RNA processing, DNA recombination, and development in B cells.

免疫球蛋白重链 ( IgH ) 位点相关的富含 G 的长非编码 RNA (SμGLT) 对于生理和病理 B 细胞 DNA 重组非常重要。我们证明 METTL3 酶催化的 N ^{6 -}甲基腺苷 (m ⁶ A) RNA 修饰驱动 RNA 外泌体对 SμGLT 的识别和 3' 末端加工，促进类别转换重组 (CSR) 并抑制染色体易位。该识别是由 MPP6 接头蛋白与核 m ⁶ A 阅读器 YTHDC1 的相互作用驱动的。 MPP6 和 YTHDC1 通过招募 AID 和 RNA 外泌体来主动转录 SμGLT 来促进 CSR。直接抑制 SμGLT 的 m ⁶ A 修饰或 m ⁶ A 阅读器 YTHDC1 会降低 CSR。此外，METTL3 是骨髓和生发中心 B 细胞发育的必需基因，可抑制 IgH 相关的异常 DNA 断裂并防止基因组不稳定。综上所述，我们提出 MPP6、m ⁶ A 修饰和 m ⁶ A 阅读器蛋白在控制长非编码 RNA 加工、DNA 重组和 B 细胞发育中的协调和核心作用。