Different mutation signatures in DNA polymerase η- and MSH6-deficient mice suggest separate roles in antibody diversification

Stella A. Martomo, William W. Yang, Robert P. Wersto, Tsuyoshi Ohkumo, Yuji Kondo, Masayuki Yokoi, Chikahide Masutani, Fumio Hanaoka, Patricia J. Gearhart

Research output: Contribution to journalArticlepeer-review

Abstract

Hypermutation in immunoglobulin genes produces a high frequency of substitutions of all four bases, which are likely generated by low-fidelity DNA polymerases. Indeed, humans deficient for DNA polymerase (pol) η have decreased substitutions of A·T base pairs in variable and switch regions. To study the role of pol η in a genetically tractable system, we created mice lacking pol η. B cells from Polh-/- mice produced normal amounts of IgG, indicating that pol η does not affect class switch recombination. Similar to their human counterparts, variable and switch regions from Polh-/- mice had fewer substitutions of A·T base pairs and correspondingly more mutations of C·G base pairs, which firmly establishes a central role for pol η in hypermutation. Notably, the location and types of substitutions differ markedly from those in Msh6-/- clones, which also have fewer A·T mutations. The data suggest that pol η preferentially synthesizes a repair patch on the nontranscribed strand, whereas MSH6 functions to generate the patch.

Original languageEnglish (US)
Pages (from-to)8656-8661
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number24
DOIs
StatePublished - Jun 14 2005

Keywords

  • Class switch recombination
  • Low-fidelity DNA polymerase
  • Mismatch repair
  • Somatic hypermutation

ASJC Scopus subject areas

  • General

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