title: Absence of DNA polymerase theta results in decreased somatic hypermutation frequency and altered mutation patterns in Ig genes.
abstract: Multiple DNA polymerases participate in somatic hypermutation of immunoglobulin (Ig) genes. Mutations at A/T are largely dependent on DNA polymerase eta (POLH) whereas mutations at C/G appear to be generated by several DNA polymerases. We have previously shown that mice expressing a catalytically inactive POLQ (Polq-inactive) have a reduction in C/G mutations. Here we have generated mice that completely lack Polq expression (Polq-null). Polq-null mice have no obvious abnormality in B or T cell differentiation, and their splenic B cells responded normally to various activation signals and underwent normal Ig gene class switching. The mutant mice mounted relatively normal immune responses against a T-dependent antigen although there was a slight decrease in antigen specific antibodies. Polq-null mice exhibited a mild reduction in the overall mutation frequency, however, in contrast to Polq-inactive mice where the reduction mostly affected mutations at C/G, Polq-null mice showed a reduction of both C/G and A/T mutations and there was a significant increase of G to C transversions. These results confirm a role for POLQ in somatic hypermutation and suggest that in the complete absence of POLQ other polymerases may functionally substitute, resulting in a mutation pattern different from that found in Polq-inactive mice.
authors.affiliation: Laboratory for Antigen Receptor Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Masuda
authors.forename: Rika
authors.initials: R
authors.lastname: Ouchida
authors.forename: Masaki
authors.initials: M
authors.lastname: Hikida
authors.forename: Manabu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.forename: Jiyang
authors.initials: J
authors.lastname: O-Wang
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D051379:Mice; D009154:Mutation; D027041:Somatic Hypermutation, Immunoglobulin; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D000097462:DNA Polymerase theta
chemical_list: D004259:DNA-Directed DNA Polymerase; D000097462:DNA Polymerase theta