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DOT1L enables Activation Induced Deaminase activity genome-wide by limiting RNAPII promoter proximal pause release

ABSTRACT: Activation induced deaminase (AID) initiates class switch recombination (CSR) and somatic hypermutation of the antibody genes but also mutates other genes, with oncogenic consequences, as a side effect. It is important to understand the mechanisms that render the antibody genes and off-target genomic loci susceptible to AID. We identify the H3K79 histone methyltransferase DOT1L as nuclear AID-proximal factor required for CSR, as well as off-target AID activity, including IgH-cMyc translocations. Mechanistically, we find that DOT1L activity restricts transcriptional pause release, as evidenced by reduced promoter-proximal RNA polymerase II (RNAPII) and increased RNAPII Serine 2 phosphorylation into the gene bodies of all H3K79-modified genes. Additional evidence suggests that widespread pause release results in abnormal transcription elongation, which can explain the variable effect of DOT1L-deficiency on H3K79-methylated gene transcript levels, depending on their original transcriptional activity and gene length. Thus, we propose that DOT1L limits transcriptional pause release, which enables AID activity genome-wide.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Javier Marcelo Di Noia

PROVIDER: MSV000092065 | MassIVE | Wed May 31 12:31:00 BST 2023

REPOSITORIES: MassIVE

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