Nature Immunology
4, 435 - 441 (2003)
Published online: 7 April 2003; | doi:10.1038/ni918
The influence of transcriptional orientation on endogenous switch region functionReiko Shinkura1, 2, Ming Tian1, 2, Michele Smith1, Katrin Chua1, Yuko Fujiwara1
& Frederick W. Alt11
Howard Hughes Medical Institute, The Children's Hospital, The Center for Blood Research, and Department of Genetics, Harvard University Medical School, Boston, MA 02115, USA. 2
These authors contributed equally to this work.
Correspondence should be addressed to Frederick W. Alt alt@enders.tch.harvard.eduImmunoglobulin heavy chain (IgH) class switch recombination (CSR) takes place between large switch (S) regions that precede exons of the constant region. The precise functions of the S region are controversial, although transcription of the S region targets CSR. We have tested the effects of deletion, inversion and replacement of the endogenous 12-kilobase S 1 region on CSR in vivo. Here we show that S1 is required for CSR, that CSR is effected by a 1-kilobase sequence that generates a G-rich transcript, and that inversion of S1 or the G-rich sequence decreases CSR. We conclude that S1 function is dependent on orientation and lacks an absolute requirement for common S region motifs. We propose that single-stranded DNA stabilized by transcription-dependent, higher order structures is a primary substrate of CSR.
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