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An evolutionarily conserved target motif for immunoglobulin class-switch recombination.
Ali A Zarrin1, Frederick W Alt, Jayanta Chaudhuri
1Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, and Department of Genetics, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Nature Immunology
|November 9, 2004
Summary
Xenopus laevis switch regions can mediate immunoglobulin class-switch recombination (CSR) without forming R-loops, suggesting an alternative mechanism. This study identifies AGCT repeats as a primordial motif targeting activation-induced cytidine deaminase (AID) via a non-R-loop pathway.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Immunoglobulin class-switch recombination (CSR) is essential for adaptive immunity, enabling antibody diversification.
- CSR in mammals typically requires transcription through GC-rich switch regions, forming R-loops that serve as substrates for activation-induced cytidine deaminase (AID).
Purpose of the Study:
- To investigate if non-mammalian switch regions, not prone to R-loop formation, can support CSR.
- To elucidate the mechanism by which the Xenopus laevis S(mu) switch region mediates CSR.
Main Methods:
- Functional replacement of mouse switch regions with Xenopus laevis S(mu) in vivo.
- In vitro transcription of the Xenopus laevis S(mu) region.
- Analysis of DNA motifs targeted by AID and replication protein A (RPA) complex.
Main Results:
- The Xenopus laevis S(mu) switch region, rich in AT and not forming R-loops, successfully mediated CSR in vivo.
- CSR mediated by Xenopus laevis S(mu) predominantly occurred within AGCT repeat regions.
- In vitro transcription assays showed targeting of these AGCT repeats by the AID-replication protein A complex.
Conclusions:
- The Xenopus laevis S(mu) switch region supports CSR independently of R-loop formation, challenging established models.
- AGCT repeats represent a primordial motif for CSR, targeting AID through a non-R-loop mechanism involving the AID-RPA complex.