Increased targeting of donor switch region and IgE in Sgamma1-deficient B cells.
Ab class switch recombination involves a recombination between two repetitive DNA sequences known as switch (S) regions that vary in length, content, and density of the repeats. Abs expressed by B cells are diversified by somatic hypermutation and class switch recombination. Both class switch recombination and somatic hypermutation are initiated by activation-induced cytidine deaminase (AID), which preferentially recognizes certain hot spots that are far more enriched in the S regions. We found that removal of the largest S region, Sgamma1 (10 kb), in mice can result in the accumulation of mutations and short-range intra-S recombination in the donor Smu region. Furthermore, elevated levels of IgE were detected in trinitrophenol-OVA-immunized mice and in anti-CD40 plus IL-4-stimulated B cells in vitro. We propose that AID availability and targeting in part might be regulated by its DNA substrate. Thus, prominently transcribed S regions, such as Sgamma1, might provide a sufficient sink for AID protein to titrate away AID from other accessible sites within or outside the Ig locus.
Department of Physiological Chemistry, Genentech, San Francisco, CA 94080, USA.
Shahram
S
Misaghi
Christopher S
CS
Garris
Yonglian
Y
Sun
Allen
A
Nguyen
Juan
J
Zhang
Andrew
A
Sebrell
Kate
K
Senger
Donghong
D
Yan
Maria N
MN
Lorenzo
Sherry
S
Heldens
Wyne P
WP
Lee
Min
M
Xu
Jiansheng
J
Wu
Laura
L
DeForge
Tao
T
Sai
Vishva M
VM
Dixit
Ali A
AA
Zarrin
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D017353:Gene Deletion; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007073:Immunoglobulin E / Q000235:genetics / Q000378:metabolism*; D007132:Immunoglobulin Isotypes / Q000235:genetics; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011995:Recombination, Genetic / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin
D007132:Immunoglobulin Isotypes; D007073:Immunoglobulin E