DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID.

ABSTRACT: Activation-induced deaminase (AID) mutates immunoglobulin genes to initiate antibody diversification by class switch recombination and somatic hypermutation but can also target non-immunoglobulin loci with oncogenic consequences. The mechanisms determining gene susceptibility to AID remain unclear. Here, we show that the H3K79 histone methyltransferase DOT1L is proximal to nuclear AID and promotes both class switch recombination and off-target AID activity, including Igh-cMyc translocations in mouse B cells. AID-mutated genes display high DOT1L activity. In the absence of DOT1L, nascent transcription largely increases despite reduced RNA Polymerase II (RNAPII) occupancy. Integrative genomic analyses reveal that DOT1L locally restricts transcription elongation velocity proportionally to H3K

SUBMITTER: Subramani PG 

PROVIDER: S-EPMC12905297 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature