DNA polymerase ζ generates tandem mutations in immunoglobulin variable regions

Huseyin Saribasak, Robert W. Maul, Zheng Cao, William W. Yang, Dominik Schenten, Sven Kracker, Patricia J. Gearhart

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Low-fidelity DNA polymerases introduce nucleotide substitutions in immunoglobulin variable regions during somatic hypermutation. Although DNA polymerase (pol) η is the major low-fidelity polymerase, other DNA polymerases may also contribute. Existing data are contradictory as to whether pol ζ is involved. We reasoned that the presence of pol η may mask the contribution of pol ζ, and therefore we generated mice deficient for pol η and heterozygous for pol ζ. The frequency and spectra of hypermutation was unaltered between Polζ +/- Polη -/- and Polζ +/+ Polη -/- clones. However, there was a decrease in tandem double-base substitutions in Polζ +/- Polη -/- cells compared with Polζ +/+ Polη -/- cells, suggesting that pol ζ generates tandem mutations. Contiguous mutations are consistent with the biochemical property of pol ζ to extend a mismatch with a second mutation. The presence of this unique signature implies that pol ζ contributes to mutational synthesis in vivo. Additionally, data on tandem mutations from wild type, Polζ +/-, Polζ -/-, Ung -/-, Msh2 -/-, Msh6 -/-, and Ung -/- Msh2 -/- clones suggest that pol ζ may function in the MSH2-MSH6 pathway.

Original languageEnglish (US)
Pages (from-to)1075-1081
Number of pages7
JournalJournal of Experimental Medicine
Volume209
Issue number6
DOIs
StatePublished - Jun 4 2012
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Saribasak, H., Maul, R. W., Cao, Z., Yang, W. W., Schenten, D., Kracker, S., & Gearhart, P. J. (2012). DNA polymerase ζ generates tandem mutations in immunoglobulin variable regions. Journal of Experimental Medicine, 209(6), 1075-1081. https://doi.org/10.1084/jem.20112234