TY - JOUR
T1 - Multiple, conserved cryptic recombination signals in VH gene segments
T2 - Detection of cleavage products only in pro-B cells
AU - Davila, Marco
AU - Liu, Feifei
AU - Cowell, Lindsay G.
AU - Lieberman, Anne E.
AU - Heikamp, Emily
AU - Patel, Anjali
AU - Kelsoe, Garnett
PY - 2007/12/24
Y1 - 2007/12/24
N2 - Receptor editing is believed to play the major role in purging newly formed B cell compartments of autoreactivity by the induction of secondary V(D)J rearrangements. In the process of immunoglobulin heavy (H) chain editing, these secondary rearrangements are mediated by direct VH-to-JH joining or cryptic recombination signals (cRSs) within VH gene segments. Using a statistical model of RS, we have identified potential cRSs within VH gene segments at conserved sites flanking complementarity-determining regions 1 and 2. These cRSs are active in extrachromosomal recombination assays and cleaved during normal B cell development. Cleavage of multiple VH cRSs was observed in the bone marrow of C57BL/6 and RAG2:GFP and μMT congenic animals, and we determined that cRS cleavage efficiencies are 30-50-fold lower than a physiological RS. cRS signal ends are abundant in pro-B cells, including those recovered from μMT mice, but undetectable in pre- or immature B cells. Thus, VH cRS cleavage regularly occurs before the generation of functional preBCR and BCR. Conservation of cRSs distal from the 3′ end of VH gene segments suggests a function for these cryptic signals other than VH gene replacement. JEM
AB - Receptor editing is believed to play the major role in purging newly formed B cell compartments of autoreactivity by the induction of secondary V(D)J rearrangements. In the process of immunoglobulin heavy (H) chain editing, these secondary rearrangements are mediated by direct VH-to-JH joining or cryptic recombination signals (cRSs) within VH gene segments. Using a statistical model of RS, we have identified potential cRSs within VH gene segments at conserved sites flanking complementarity-determining regions 1 and 2. These cRSs are active in extrachromosomal recombination assays and cleaved during normal B cell development. Cleavage of multiple VH cRSs was observed in the bone marrow of C57BL/6 and RAG2:GFP and μMT congenic animals, and we determined that cRS cleavage efficiencies are 30-50-fold lower than a physiological RS. cRS signal ends are abundant in pro-B cells, including those recovered from μMT mice, but undetectable in pre- or immature B cells. Thus, VH cRS cleavage regularly occurs before the generation of functional preBCR and BCR. Conservation of cRSs distal from the 3′ end of VH gene segments suggests a function for these cryptic signals other than VH gene replacement. JEM
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U2 - 10.1084/jem.20071224
DO - 10.1084/jem.20071224
M3 - Article
C2 - 18056287
AN - SCOPUS:37549037403
SN - 0022-1007
VL - 204
SP - 3195
EP - 3208
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 13
ER -