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Molecular and Cellular Biology, March 2005, p. 1730-1736, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1730-1736.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Fine-Structure Analysis of Activation-Induced Deaminase Accessibility to Class Switch Region R-Loops

Kefei Yu,1,2 Deepankar Roy,1,2 Melina Bayramyan,1,3 Ian S. Haworth,1,3 and Michael R. Lieber1,2*

Department of Biochemistry and Molecular Biology,1 Departments of Pathology, Molecular Microbiology and Immunology, and Biological Sciences, University of Southern California Keck School of Medicine,2 Department of Pharmaceutical Sciences, University of Southern California School of Pharmacy, Los Angeles, California3

Received 2 October 2004/ Returned for modification 15 November 2004/ Accepted 24 November 2004

Activation-induced deaminase (AID) is essential for class switch recombination and somatic hypermutation, and it has the ability to deaminate single-stranded DNA at cytidines. Mammalian class switch regions form R-loops upon transcription in the physiological orientation. The displaced DNA strand of an R-loop is forced to wrap around the RNA-DNA hybrid; hence, it may not have complete exposure to proteins. A fundamental question concerns the extent to which AID is accessible to the displaced strand of a transcription-generated R-loop. We used a minimal R-loop to carry out high-resolution analysis of the precise locations of AID action. We found that AID deaminates on the displaced DNA strand across the entire length of the R-loop. Displaced strand locations with a WRC (where W is A or T and R is A or G) sequence are preferred targets, but there are clear exceptions. These WRC deviations may be due to steric constraints on the accessibility of AID to these sites as the displaced strand twists around the RNA-DNA duplex. This phenomenon may explain the lack of WRC site preference at the mutations surrounding class switch recombination junctions.

* Corresponding author. Mailing address: USC Norris Cancer Ctr., Rm. 5428, 1441 Eastlake Ave., MC9176, Los Angeles, CA 90033. Phone: (323) 865-0568. Fax: (323) 865-3019. E-mail: lieber{at}usc.edu.

Molecular and Cellular Biology, March 2005, p. 1730-1736, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1730-1736.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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