TY - JOUR
T1 - The Mismatch Repair Protein Msh6 Influences the In Vivo AID Targeting to the Ig Locus
AU - Li, Ziqiang
AU - Zhao, Chunfang
AU - Iglesias-Ussel, Maria D.
AU - Polonskaya, Zhanna
AU - Zhuang, Min
AU - Yang, Guozhe
AU - Luo, Zhonghui
AU - Edelmann, Winfried
AU - Scharff, Matthew D.
N1 - Funding Information:
We thank Dr. T. Honjo for advice on ChIP experiments in switch regions, J.U. Peled for help with class switching experiments, and Dr. B.K. Birshtein and other members of Scharff laboratory for critically reading the manuscript. This work was supported by grants from the National Institutes of Health to W.E. (CA76329 and CA93484) and to M.D.S. (CA 72649, CA102705, and AI57158), who is also supported by the Harry Eagle Chair provided by the National Women's Division of the Albert Einstein College of Medicine. M.D.I.-U was a fellow of the Ministerio de Educacion, Cultura y Deporte (Spain) and is currently supported by a Fellowship from the Northeast Biodefense Center (AI57158). Z.L. was supported by a Cancer Research Institute Postdoctoral Fellowship and is currently a Special Fellow of The Leukemia & Lymphoma Society.
PY - 2006/4
Y1 - 2006/4
N2 - 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 (Msh6TD/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, Msh6TD/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.
AB - 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 (Msh6TD/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, Msh6TD/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.
KW - MOLIMMUNO
UR - https://www.scopus.com/pages/publications/33646015672
UR - https://www.scopus.com/pages/publications/33646015672#tab=citedBy
U2 - 10.1016/j.immuni.2006.02.011
DO - 10.1016/j.immuni.2006.02.011
M3 - Article
C2 - 16618598
AN - SCOPUS:33646015672
SN - 1074-7613
VL - 24
SP - 393
EP - 403
JO - Immunity
JF - Immunity
IS - 4
ER -
SDG 3 Good Health and Well-being