SRP325611 PRJNA693506 Mechanism of noncoding RNA associated N6-Methyladenosine recognition by an RNA processing complex during IgH DNA recombination RNA modifications are important for RNA diversity, but the mechanism(s) of recognition and direct biological effects remain elusive. Immunoglobulin heavy chain (IgH) locus-associated G-rich long noncoding RNA (SmuGLT) 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 SmuGLT 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 transcribing SmuGLT. Direct suppression of m6A modification of SmuGLT 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 a coordinated function and central role for MPP6, m6A modification, and m6A reader proteins in controlling DNA recombination in B cells, long noncoding RNA processing, and immune system homeostasis. Mus musculus