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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900135v1 183/2/1222    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Eccleston, J. Articles by Selsing, E. PubMed PubMed Citation Articles by Eccleston, J. Articles by Selsing, E.

Class Switch Recombination Efficiency and Junction Microhomology Patterns in Msh2-, Mlh1-, and Exo1-Deficient Mice Depend on the Presence of µ Switch Region Tandem Repeats¹

Jennifer Eccleston^*, Carol E. Schrader, Karen Yuan^*, Janet Stavnezer and Erik Selsing^2,*

^* Immunology Program and Department of Pathology, Tufts University School of Medicine, Boston, MA 02111; and Program in Immunology and Virology and Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655

The Msh2 mismatch repair (MMR) protein is critical for class switch recombination (CSR) events that occur in mice that lack the Sµ tandem repeat (SµTR) region (SµTR^–/– mice). The pattern of microhomology among switch junction sites in Msh2-deficient mice is also dependent on the presence or absence of SµTR sequences. It is not known whether these CSR effects reflect an individual function of Msh2 or the function of Msh2 within the MMR machinery. In the absence of the SµTR sequences, Msh2 deficiency nearly ablates CSR. We now show that Mlh1 or Exo1 deficiencies also eliminate CSR in the absence of the SµTR. Furthermore, in SµTR^–/– mice, deficiencies of Mlh1 or Exo1 result in increased switch junction microhomology as has also been seen with Msh2 deficiency. These results are consistent with a CSR model in which the MMR machinery is important in processing DNA nicks to produce double-stranded breaks, particularly in sequences where nicks are infrequent. We propose that double-stranded break paucity in MMR-deficient mice leads to increased use of an alternative joining pathway where microhomologies are important for CSR break ligation. Interestingly, when the SµTR region is present, deficiency of Msh2 does not lead to the increased microhomology seen with Mlh1 or Exo1 deficiencies, suggesting that Msh2 might have an additional function in CSR. It is also possible that the inability to initiate MMR in the absence of Msh2 results in CSR junctions with less microhomology than joinings that occur when MMR is initiated but then proceeds abnormally due to Mlh1 or Exo1 deficiencies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health Grants AI24465 (to E.S.), AI23283 (to J.S.), and AI65639 (to C.E.S.) and by the Eshe Foundation.

² Address correspondence and reprint requests to Dr. Erik Selsing, Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 02111. E-mail address: Erik.selsing{at}tufts.edu

³ Abbreviations used in this paper: CSR, class switch recombination; AEJ, alternative end joining; AID, activation-induced cytidine deaminase; MMR, mismatch repair; NHEJ, nonhomologous end joining; S region, switch region; SµTR, Sµ tandem repeat; UNG, uracil DNA glycosylase; WT, wild type.

⁴ The online version of this article contains supplemental material.