Functional overlap in the cis-acting regulation of the V(D)J recombination at the TCRβ locus

Academic Article

Abstract

  • The second exon of lymphocyte antigen receptor genes is assembled in developing lymphocytes from component V, J and, in some cases, D gene segments through the process of V(D)J recombination. This process is initiated by an endonuclease comprised of the Rag-1 and Rag-2 proteins, collectively referred to as Rag. Rag binds to recombination signals (RSs) and catalyzes the pair-wise introduction of DNA double strand breaks (DSBs) at recombining gene segments. DNA cleavage by Rag is restricted both by intrinsic features of RSs, as well as the activity of other cis-acting elements, such as promoters and enhancers that regulate the accessibility of gene segments to Rag. In the TCRβ locus, accessibility of the Dβ1-Jβ1 gene segment cluster relies on the function of an enhancer, Eβ, and a promoter, PDβ1. Here we demonstrate that deletion of a small genomic region containing five of the six Jβ1 gene segments, but no known transcriptional regulatory elements, leads to a marked decrease in transcription and rearrangements involving the Dβ1 and Jβ1.1 gene segments. Surprisingly, point mutations in the RS of the Jβ1.1 gene segment not only impact Rag cleavage, but also lead to diminished transcription through the Dβ1-Jβ1 gene segment cluster. Our findings demonstrate that cis-acting elements that regulate transcription and accessibility of the TCRβ locus may functionally overlap with RS sequences, which are known primarily to direct Rag-mediated cleavage. © 2008 Elsevier Ltd. All rights reserved.
  • Authors

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    Digital Object Identifier (doi)

    Author List

  • Khor B; Mahowald GK; Khor K; Sleckman BP
  • Start Page

  • 321
  • End Page

  • 326
  • Volume

  • 46
  • Issue

  • 3