DNA polymerase ? generates tandem mutations in immunoglobulin variable regions.

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

SUBMITTER: Saribasak H 

PROVIDER: S-EPMC3371727 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature