The mismatch repair protein Msh6 influences the in vivo AID targeting to the Ig locus.
Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase (AID), which preferentially deaminates deoxycytidines at WRC (W = A/T, R = A/G) motifs in vitro. The mechanisms responsible for targeting AID and for organizing the queue of enzymes involved in vivo have been elusive. Here, we examined point mutant knockin Msh6 mice (Msh6(TD/TD)), which lack the second phase of SHM but retain all the proteins involved, and found that AID was frequently targeted to non-WRC motifs. Unexpectedly, by comparing SHM and CSR in wild-type, Msh6(TD/TD), and age-matched Msh6(-/-) mice, we discovered that the presence of Msh6 protein influenced the AID targeting in phase one of SHM and mediated the proper targeting of recombination sites in CSR in vivo. Our data suggest that Msh6 plays a scaffolding role in the first phase of SHM, in addition to its enzymatic role in the second phase of SHM.
Li
Ziqiang
Z
Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. zli@aecom.yu.edu
Zhao
Chunfang
C
Iglesias-Ussel
Maria D
MD
Polonskaya
Zhanna
Z
Zhuang
Min
M
Yang
Guozhe
G
Luo
Zhonghui
Z
Edelmann
Winfried
W
Scharff
Matthew D
MD
D000818:Animals; D001483:Base Sequence; D043525:Cytosine Deaminase / Q000276:immunology / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005803:Genes, Immunoglobulin / Q000235:genetics*; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D027041:Somatic Hypermutation, Immunoglobulin
D004268:DNA-Binding Proteins; C102997:Msh6 protein, mouse; D043525:Cytosine Deaminase