A role for the MutL mismatch repair Mlh3 protein in immunoglobulin class switch DNA recombination and somatic hypermutation. Academic Article uri icon

Overview

MeSH

  • Animals
  • B-Lymphocytes
  • Base Pair Mismatch
  • Base Sequence
  • Cell Cycle
  • Cells, Cultured
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Recombination, Genetic
  • Sequence Alignment

MeSH Major

  • Carrier Proteins
  • DNA
  • DNA Repair
  • Immunoglobulin Class Switching
  • Somatic Hypermutation, Immunoglobulin

abstract

  • Class switch DNA recombination (CSR) and somatic hypermutation (SHM) are central to the maturation of the Ab response. Both processes involve DNA mismatch repair (MMR). MMR proteins are recruited to dU:dG mispairs generated by activation-induced cytidine deaminase-mediated deamination of dC residues, thereby promoting S-S region synapses and introduction of mismatches (mutations). The MutL homolog Mlh3 is the last complement of the mammalian set of MMR proteins. It is highly conserved in evolution and is essential to meiosis and microsatellite stability. We used the recently generated knockout mlh3(-/-) mice to address the role of Mlh3 in CSR and SHM. We found that Mlh3 deficiency alters both CSR and SHM. mlh3(-/-) B cells switched in vitro to IgG and IgA but displayed preferential targeting of the RGYW/WRCY (R = A or G, Y = C or T, W = A or T) motif by Sgamma1 and Sgamma3 breakpoints and introduced more insertions and fewer donor/acceptor microhomologies in Smu-Sgamma1 and Smu-Sgamma3 DNA junctions, as compared with mlh3(+/+) B cells. mlh3(-/-) mice showed only a slight decrease in the frequency of mutations in the intronic DNA downstream of the rearranged J(H)4 gene. However, the residual mutations were altered in spectrum. They comprised a decreased proportion of mutations at dA/dT and showed preferential RGYW/WRCY targeting by mutations at dC/dG. Thus, the MMR Mlh3 protein plays a role in both CSR and SHM.

publication date

  • May 1, 2006

has subject area

  • Animals
  • B-Lymphocytes
  • Base Pair Mismatch
  • Base Sequence
  • Carrier Proteins
  • Cell Cycle
  • Cells, Cultured
  • DNA
  • DNA Repair
  • Immunoglobulin Class Switching
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Recombination, Genetic
  • Sequence Alignment
  • Somatic Hypermutation, Immunoglobulin

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed ID

  • 16622010

Additional Document Info

start page

  • 5426

end page

  • 5437

volume

  • 176

number

  • 9