TY - JOUR
T1 - Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification
AU - Li, Ziqiang
AU - Scherer, Stefan J.
AU - Ronai, Diana
AU - Iglesias-Ussel, Maria D.
AU - Peled, Jonathan U.
AU - Bardwell, Philip D.
AU - Zhuang, Min
AU - Lee, Kye Ryoung
AU - Martin, Alberto
AU - Edelmann, Winfried
AU - Scharff, Matthew D.
PY - 2004/7/5
Y1 - 2004/7/5
N2 - Somatic hypermutation and class switch recombination (CSR) contribute to the somatic diversification of antibodies. It has been shown that MutS homologue (Msh)6 (in conjunction with Msh2) but not Msh3 is involved in generating A/T base substitutions in somatic hypermutation. However, their roles in CSR have not yet been reported. Here we show that Msh6-/- mice have a decrease in CSR, whereas Msh3-/- mice do not. When switch regions were analyzed for mutations, deficiency in Msh6 was associated with an increase in transition mutations at G/C basepairs, mutations at RGYW/WRCY hotspots, and a small increase in the targeting of G/C bases. In addition, Msh6-/- mice exhibited an increase in the targeting of recombination sites to GAGCT/GGGGT consensus repeats and hotspots in Sγ3 but not in Sμ. In contrast to Msh2-/- mice, deficiency in Msh6 surprisingly did not change the characteristics of Sμ-Sγ3 switch junctions. However, Msh6-/- mice exhibited a change in the positioning of Sμ and Sγ3 junctions. Although none of these changes were seen in Msh3 -/- mice, they had a higher percentage of large inserts in their switch junctions. Together, our data suggest that MutS homologues Msh2, Msh3, and Msh6 play overlapping and distinct roles during antibody diversification processes.
AB - Somatic hypermutation and class switch recombination (CSR) contribute to the somatic diversification of antibodies. It has been shown that MutS homologue (Msh)6 (in conjunction with Msh2) but not Msh3 is involved in generating A/T base substitutions in somatic hypermutation. However, their roles in CSR have not yet been reported. Here we show that Msh6-/- mice have a decrease in CSR, whereas Msh3-/- mice do not. When switch regions were analyzed for mutations, deficiency in Msh6 was associated with an increase in transition mutations at G/C basepairs, mutations at RGYW/WRCY hotspots, and a small increase in the targeting of G/C bases. In addition, Msh6-/- mice exhibited an increase in the targeting of recombination sites to GAGCT/GGGGT consensus repeats and hotspots in Sγ3 but not in Sμ. In contrast to Msh2-/- mice, deficiency in Msh6 surprisingly did not change the characteristics of Sμ-Sγ3 switch junctions. However, Msh6-/- mice exhibited a change in the positioning of Sμ and Sγ3 junctions. Although none of these changes were seen in Msh3 -/- mice, they had a higher percentage of large inserts in their switch junctions. Together, our data suggest that MutS homologues Msh2, Msh3, and Msh6 play overlapping and distinct roles during antibody diversification processes.
KW - Isotype switching
KW - Mismatch repair
KW - Somatic hypermutation
KW - Switch region mutation
KW - Switching junction
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U2 - 10.1084/jem.20040355
DO - 10.1084/jem.20040355
M3 - Article
C2 - 15238604
AN - SCOPUS:3142674907
SN - 0022-1007
VL - 200
SP - 47
EP - 59
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -