A source of the single-stranded DNA substrate for activation-induced deaminase during somatic hypermutation

Xiaohua Wang, Manxia Fan, Susan Kalis, Lirong Wei, Matthew D. Scharff

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

During somatic hypermutation (SHM), activation-induced deaminase (AID) mutates deoxycytidine on single-stranded DNA (ssDNA) generated by the transcription machinery, but the detailed mechanism remains unclear. Here we report a higher abundance of RNA polymerase II (Pol II) at the immunoglobulin heavy-chain variable (Igh-V) region compared with the constant region and partially transcribed Igh RNAs, suggesting a slower Pol II progression at Igh-V that could result in some early/premature transcription termination after prolonged pausing/stalling of Pol II. Knocking down RNA-exosome complexes, which could decrease premature transcription termination, leads to decreased SHM. Knocking down Spt5, which can augment premature transcription termination, leads to increase in both, SHM and the abundance of ssDNA substrates. Collectively, our data support the model that, following the reduction of Pol II progression (pausing or stalling) at the Igh-V, additional steps such as premature transcription termination are involved in providing ssDNA substrates for AID during SHM.

Original languageEnglish (US)
Article number4137
JournalNature communications
Volume5
DOIs
StatePublished - Jun 13 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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