TY - JOUR
T1 - Normal hypermutation in antibody genes from congenic mice defective for DNA polymerase ι
AU - Martomo, Stella A.
AU - Yang, William W.
AU - Vaisman, Alexandra
AU - Maas, Alex
AU - Yokoi, Masayuki
AU - Hoeijmakers, Jan H.
AU - Hanaoka, Fumio
AU - Woodgate, Roger
AU - Gearhart, Patricia J.
N1 - Funding Information:
We thank I. Rogozin for statistical analyses; J. Chrest, C. Morris, and R. Wersto for flow cytometry; R. Hendriks for mouse tissue; H. Roest for mouse breeding; and D. Wilson and R. Brosh for comments. This work was supported, in part, by the NIH Intramural Research program.
PY - 2006/3/7
Y1 - 2006/3/7
N2 - Several low fidelity DNA polymerases participate in generating mutations in immunoglobulin genes. Polymerase η is clearly involved in the process by causing substitutions of A:T base pairs, whereas polymerase ι has a controversial role. Although the frequency of mutations was decreased in the BL2 cell line deficient for polymerase ι, hypermutation was normal in the 129 strain of mice, which has a natural nonsense mutation in the Poli gene. It is possible that the mice compensated for the defect over time, or that polymerase η substituted in the absence of polymerase ι. To examine polymerase ι in a genetically defined background, we backcrossed the 129 nonsense mutation to the C57BL/6 strain for six generations. Class switch recombination and hypermutation were studied in these mice and in congenic mice doubly deficient for both polymerases ι and η. The absence of both polymerases did not affect production of IgG1, indicating that these enzymes are not involved in switch recombination. Poli-/-F6 mice had the same types of nucleotide substitutions in variable genes as their C57BL/6 counterparts, and mice doubly deficient for polymerases ι and η had the same mutational spectrum as Polh-/- mice. Thus, polymerase ι did not contribute to the mutational spectra, even in the absence of polymerase η.
AB - Several low fidelity DNA polymerases participate in generating mutations in immunoglobulin genes. Polymerase η is clearly involved in the process by causing substitutions of A:T base pairs, whereas polymerase ι has a controversial role. Although the frequency of mutations was decreased in the BL2 cell line deficient for polymerase ι, hypermutation was normal in the 129 strain of mice, which has a natural nonsense mutation in the Poli gene. It is possible that the mice compensated for the defect over time, or that polymerase η substituted in the absence of polymerase ι. To examine polymerase ι in a genetically defined background, we backcrossed the 129 nonsense mutation to the C57BL/6 strain for six generations. Class switch recombination and hypermutation were studied in these mice and in congenic mice doubly deficient for both polymerases ι and η. The absence of both polymerases did not affect production of IgG1, indicating that these enzymes are not involved in switch recombination. Poli-/-F6 mice had the same types of nucleotide substitutions in variable genes as their C57BL/6 counterparts, and mice doubly deficient for polymerases ι and η had the same mutational spectrum as Polh-/- mice. Thus, polymerase ι did not contribute to the mutational spectra, even in the absence of polymerase η.
KW - Class switch recombination
KW - Congenic mice
KW - Immunoglobulins
KW - Pol η
KW - Pol ι
KW - Somatic hypermutation
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U2 - 10.1016/j.dnarep.2005.12.006
DO - 10.1016/j.dnarep.2005.12.006
M3 - Article
C2 - 16443401
AN - SCOPUS:32644476870
SN - 1568-7864
VL - 5
SP - 392
EP - 398
JO - DNA Repair
JF - DNA Repair
IS - 3
ER -