The translesion DNA polymerase θ plays a dominant role in immunoglobulin gene somatic hypermutation

Hong Zan, Naoko Shima, Zhenming Xu, Ahmed Al-Qahtani, Albert J. Evinger, Yuan Zhong, John C. Schimenti, Paolo Casali

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Immunoglobulin (Ig) somatic hypermutation (SHM) critically underlies the generation of high-affinity antibodies. Mutations can be introduced by error-prone polymerases such as polymerase ζ (Rev3), a mispair extender, and polymerase ν, a mispair inserter with a preference for dA/dT, while repairing DNA lesions initiated by AID-mediated deamination of dC to yield dU:dG mismatches. The partial impairment of SHM observed in the absence of these polymerases led us to hypothesize a main role for another translesion DNA polymerase. Here, we show that deletion in C57BL/6J mice of the translesion polymerase θ, which possesses a dual nucleotide mispair inserter-extender function, results in greater than 60% decrease of mutations in antigen-selected V186.2DJH transcripts and greater than 80% decrease in mutations in the Ig H chain intronic JH4-iEμ sequence, together with significant alterations in the spectrum of the residual mutations. Thus, polymerase θ plays a dominant role in SHM, possibly by introducing mismatches while bypassing abasic sites generated by UDG-mediated deglycosylation of AID-effected dU, by extending DNA past such abasic sites and by synthesizing DNA during dU:dG mismatch repair.

Original languageEnglish (US)
Pages (from-to)3757-3769
Number of pages13
JournalEMBO Journal
Volume24
Issue number21
DOIs
StatePublished - Nov 2 2005

Keywords

  • Antibody
  • DNA polymerase θ
  • DNA repair
  • Somatic hypermutation
  • Translesion DNA polymerase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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