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 Previous Article

Molecular and Cellular Biology, August 2007, p. 5921-5932, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00702-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Sequence Dependence of Chromosomal R-Loops at the Immunoglobulin Heavy-Chain Sµ Class Switch Region{triangledown} ,{dagger}

Feng-Ting Huang,1 Kefei Yu,1 Barbara B. Balter,3 Erik Selsing,3 Zeliha Oruc,4 Ahmed Amine Khamlichi,4 Chih-Lin Hsieh,2 and Michael R. Lieber1*

Departments of Pathology, of Biochemistry and Molecular Biology, of Molecular Microbiology and Immunology, and of Biological Sciences,1 Departments of Urology and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, MC9176, Los Angeles, California 90089-9176,2 Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, Massachusetts 02111,3 CNRS UMR 5089-IPBS, Equipe Instabilité Génétique et Régulation Transcriptionnelle, 205 route de Narbonne, 31077 Toulouse Cedex, France4

Received 20 April 2007/ Returned for modification 29 May 2007/ Accepted 1 June 2007

The mechanism by which the cytidine deaminase activation-induced deaminase (AID) acts at immunoglobulin heavy-chain class switch regions during mammalian class switch recombination (CSR) remains unclear. R-loops have been proposed as a basis for this targeting. Here, we show that the difference between various forms of the Sµ locus that can or cannot undergo CSR correlates well with the locations and detectability of R-loops. The Sµ R-loops can initiate hundreds of base pairs upstream of the core repeat switch regions, and the area where the R-loops initiate corresponds to the zone where the AID mutation frequency begins to rise, despite a constant density of WRC sites in this region. The frequency of R-loops is 1 in 25 alleles, regardless of the presence of the core Sµ repeats, again consistent with the initiation of most R-loops upstream of the core repeats. These findings explain the surprisingly high levels of residual CSR in B cells from mice lacking the core Sµ repeats but the marked reduction in CSR in mice with deletions of the region upstream of the core Sµ repeats. These studies also provide the first analysis of how R-loop formation in the eukaryotic chromosome depends on the DNA sequence.

* Corresponding author. Mailing address: Norris Comprehensive Cancer Center, Rm. 5428, University of Southern California, 1441 Eastlake Ave., MC9176, Los Angeles, CA 90089-9176. Phone: (323) 865-0568. Fax: (323) 865-3019. E-mail: lieber{at}usc.edu

{triangledown} Published ahead of print on 11 June 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2007, p. 5921-5932, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00702-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, L., Wuerffel, R., Feldman, S., Khamlichi, A. A., Kenter, A. L. (2009). S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination. JEM 206: 1817-1830 [Abstract] [Full Text]  
  • Rajagopal, D., Maul, R. W., Ghosh, A., Chakraborty, T., Khamlichi, A. A., Sen, R., Gearhart, P. J. (2009). Immunoglobulin switch {micro} sequence causes RNA polymerase II accumulation and reduces dA hypermutation. JEM 206: 1237-1244 [Abstract] [Full Text]  
  • Roy, D., Lieber, M. R. (2009). G Clustering Is Important for the Initiation of Transcription-Induced R-Loops In Vitro, whereas High G Density without Clustering Is Sufficient Thereafter. Mol. Cell. Biol. 29: 3124-3133 [Abstract] [Full Text]  
  • Canugovi, C., Samaranayake, M., Bhagwat, A. S. (2009). Transcriptional pausing and stalling causes multiple clustered mutations by human activation-induced deaminase. FASEB J. 23: 34-44 [Abstract] [Full Text]  
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  • Roy, D., Yu, K., Lieber, M. R. (2008). Mechanism of R-Loop Formation at Immunoglobulin Class Switch Sequences. Mol. Cell. Biol. 28: 50-60 [Abstract] [Full Text]  


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