| First Author | Stone JL | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 5 | Pages | 2266-75 |
| PubMed ID | 22287717 | Mgi Jnum | J:181246 |
| Mgi Id | MGI:5310656 | Doi | 10.4049/jimmunol.1002931 |
| Citation | Stone JL, et al. (2012) DNA Double-Strand Breaks Relieve USF-Mediated Repression of Dbeta2 Germline Transcription in Developing Thymocytes. J Immunol 188(5):2266-75 |
| abstractText | Activation of germline promoters is central to V(D)J recombinational accessibility, driving chromatin remodeling, nucleosome repositioning, and transcriptional read-through of associated DNA. We have previously shown that of the two TCRbeta locus (Tcrb) D segments, Dbeta1 is flanked by an upstream promoter that directs its transcription and recombinational accessibility. In contrast, transcription within the DJbeta2 segment cluster is initially restricted to the J segments and only redirected upstream of Dbeta2 after D-to-J joining. The repression of upstream promoter activity prior to Tcrb assembly correlates with evidence that suggests DJbeta2 recombination is less efficient than that of DJbeta1. Because inefficient DJbeta2 assembly offers the potential for V-to-DJbeta2 recombination to rescue frameshifted V-to-DJbeta1 joints, we wished to determine how Dbeta2 promoter activity is modulated upon Tcrb recombination. In this study, we show that repression of the otherwise transcriptionally primed 5'Dbeta2 promoter requires binding of upstream stimulatory factor (USF)-1 to a noncanonical E-box within the Dbeta2 12-recombination signal sequence spacer prior to Tcrb recombination. USF binding is lost from both rearranged and germline Dbeta2 sites in DNA-dependent protein kinase, catalytic subunit-competent thymocytes. Finally, genotoxic dsDNA breaks lead to rapid loss of USF binding and gain of transcriptionally primed 5'Dbeta2 promoter activity in a DNA-dependent protein kinase, catalytic subunit-dependent manner. Together, these data suggest a mechanism by which V(D)J recombination may feed back to regulate local Dbeta2 recombinational accessibility during thymocyte development. |
