Somatic hypermutation (SHM) and class switch recombination (CSR) diversify immunoglobulin (Ig) genes and are initiated by the activation-induced deaminase (AID), a single-stranded DNA cytidine deaminase thought to engage its substrate during RNA polymerase II (RNAPII) transcription. Through a genetic screen, we identified numerous potential factors involved in SHM, including elongation factor 1 homolog (ELOF1), a component of the RNAPII elongation complex that functions in transcription-coupled nucleotide excision repair (TC-NER) and transcription elongation. Loss of ELOF1 compromises SHM, CSR, and AID action in mammalian B cells and alters RNAPII transcription by reducing RNAPII pausing downstream of transcription start sites and levels of serine 5 but not serine 2 phosphorylated RNAPII throughout transcribed genes. ELOF1 must bind to RNAPII to be a proximity partner for AID and to function in SHM and CSR, and TC-NER is not required for SHM. We propose that ELOF1 helps create the appropriate stalled RNAPII substrate on which AID acts.

Department of Immunobiology Yale School of Medicine 300 Cedar Street Box 208011 New Haven CT 06520 8011 USA

Department of Microbial Pathogenesis Yale University School of Medicine New Haven CT USA; Howard Hughes Medical Institute New Haven CT USA

Department of Molecular Biophysics and Biochemistry Yale University New Haven CT USA; Institute of Biomolecular Design and Discovery Yale University West Haven CT USA

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Videnska 1083 14220 Prague 4 Czech Republic

Key Laboratory of Multi Cell Systems Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell Science Chinese Academy of Sciences Shanghai China

Laboratory of Genome Integrity National Cancer Institute NIH Bethesda MD USA

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bioRxiv. 2024 Sep 26:2024.09.24.614732. doi: 10.1101/2024.09.24.614732. PubMed

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