TCRβ Feedback Signals Inhibit the Coupling of Recombinationally Accessible Vβ14 Segments with DJβ Complexes

Yang-Iott, Katherine; Carpenter, Andrea C.; Rowh, Marta; Steinel, Natalie C.; Brady, Brenna L.; Hochedlinger, Konrad; Jaenisch, Rudolf; Bassing, Craig H.

doi:10.4049/jimmunol.0900723

Cited by 18 publications

(22 citation statements)

References 74 publications

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“…A particularly vexing issue is V β 14-to-DJ β recombination, since, unlike all other V β gene segments, V β 14 is located near D β and J β gene segments and its accessibility is not downregulated by pre-TCR signaling and is apparently high in DP thymocytes (17, 39–41). Since D β and J β segments are also accessible and support RAG1/2 binding in DP thymocytes (42), the suppression of V β 14 rearrangement may depend on unique features of inversional rearrangement (40) or of the V β 14 RSS (41). …”

Section: Discussionmentioning

confidence: 99%

Regulation of TCRβ Allelic Exclusion by Gene Segment Proximity and Accessibility

Kondilis-Mangum

Shih

Mahowald

et al. 2011

The Journal of Immunology

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Antigen receptor loci are regulated to promote allelic exclusion, but the mechanisms are not well understood. Assembly of a functional T cell receptor (TCR) β chain gene triggers feedback inhibition of Vβ-to-DJβ recombination in double positive (DP) thymocytes which correlates with reduced Vβ chromatin accessibility and a locus conformational change that separates Vβ from DJβ gene segments. We previously generated a Tcrb allele that maintained Vβ accessibility but was still subject to feedback inhibiton in DP thymocytes. We have now further analyzed the contributions of chromatin accessibility and locus conformation to feedback inhibition using two novel TCR alleles. We show that reduced Vβ accessibility and increased distance between Vβ and DJβ gene segments both enforce feedback inhibition in DP thymocytes.

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Section: Discussionmentioning

confidence: 99%

Regulation of TCRβ Allelic Exclusion by Gene Segment Proximity and Accessibility

Kondilis-Mangum

Shih

Mahowald

et al. 2011

The Journal of Immunology

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“…However, it remained possible that USF-1 was retained in Rxβ DP cells because of accelerated DN development in the presence of the Tcrb transgene (15, 40). To exclude this possibility, we assessed USF-1 binding (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Though Dβ RSS sequence strongly influences the order of gene segment assembly (5, 13, 14), the recombinational accessibility of individual RSSs is dependent on their chromosomal location (15) and the activity of associated germline promoters. Deletion of the Dβ1-associated promoter, PDβ1, alters nucleosomal phasing across the Dβ1 5'RSS (9) and specifically impairs Tcrb Dβ1-to-Jβ recombination (16, 17) without affecting recombination at the downstream DJβ2 gene segment cluster (17).…”

Section: Introductionmentioning

confidence: 99%

DNA Double-Strand Breaks Relieve USF-Mediated Repression of Dβ2 Germline Transcription in Developing Thymocytes

Stone

McMillan

Skaar

et al. 2012

The Journal of Immunology

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Activation of germline promoters is central to V(D)J recombinational accessibility, driving chromatin remodeling, nucleosome repositioning and transcriptional readthrough of associated DNA. We have previously shown that of the 2 Tcrb D segments, Dβ1 is flanked by an upstream promoter that directs its transcription and recombinational accessibility. In contrast, transcription within the DJβ2 segment cluster is initially restricted to the J segments and only redirected upstream of Dβ2 after D-to-J joining. The repression of upstream promoter activity prior to Tcrb assembly correlates with evidence that suggests DJβ2 recombination is less efficient than that of DJβ1. Since inefficient DJβ2 assembly offers the potential for V-to-DJβ2 recombination to rescue frameshifted V-to-DJβ1 joints, we wished to determine how Dβ2 promoter activity is modulated upon Tcrb recombination. Here, we show that repression of the otherwise transcriptionally primed 5'Dβ2 promoter (5'PDβ2) requires binding of USF-1 to a non-canonical E-box within the Dβ2 12-RSS spacer prior to Tcrb recombination. USF binding is lost from both rearranged and germline Dβ2 sites in DNA-PKcs-competent thymocytes. Finally, genotoxic double-stranded DNA breaks lead to rapid loss of USF binding and gain of 5'PDβ2 activity in a DNA-PKcs-dependent manner. Together, these data suggest a mechanism by which V(D)J recombination may feedback to regulate local Dβ2 recombinational accessibility during thymocyte development.

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“…As a means to induce DSBs, we exposed thymocytes to IR since this type of radiation induces DSBs and IR was used to demonstrate DSBs signal downregulation of Cyclin D1 protein levels in non-lymphoid cells. [11][12][13][14][15] To circumvent potential loss of Cyclin D3 expression from DSB-induced apoptosis or DSB-induced feedback inhibition of Tcrb recombination, [18][19][20] we used mice expressing the pro-survival EmBCL2 transgene and the Vb14 NT pre-assembled functional Tcrb gene. Although we could detect Cyclin D3 protein in total thymocytes, we found removal of these immature T cells from the thymus caused loss of Cyclin D3 protein even without IR exposure.…”

Section: Resultsmentioning

confidence: 99%

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

et al. 2016

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Mammalian cells are thought to protect themselves and their host organisms from DNA double strand breaks (DSBs) through universal mechanisms that restrain cellular proliferation until DNA is repaired. The Cyclin D3 protein drives G1-to-S cell cycle progression and is required for proliferation of immature T and B cells and of mature B cells during a T cell-dependent immune response. We demonstrate that mouse thymocytes and pre-B cells, but not mature B cells, repress Cyclin D3 protein levels in response to DSBs. This response requires the ATM protein kinase that is activated by DSBs. Cyclin D3 protein loss in thymocytes coincides with decreased association of Cyclin D3 mRNA with the HuR RNA binding protein that ATM regulates. HuR inactivation reduces basal Cyclin D3 protein levels without affecting Cyclin D3 mRNA levels, indicating that thymocytes repress Cyclin D3 expression via ATM-dependent inhibition of Cyclin D3 mRNA translation. In contrast, ATM-dependent transcriptional repression of the Cyclin D3 gene represses Cyclin D3 protein levels in pre-B cells. Retrovirus-driven Cyclin D3 expression is resistant to transcriptional repression by DSBs; this prevents pre-B cells from suppressing Cyclin D3 protein levels and from inhibiting DNA synthesis to the normal extent following DSBs. Our data indicate that immature B and T cells use lymphocyte lineage-and developmental stage-specific mechanisms to inhibit Cyclin D3 protein levels and thereby help prevent cellular proliferation in response to DSBs. We discuss the relevance of these cellular context-dependent DSB response mechanisms in restraining proliferation, maintaining genomic integrity, and suppressing malignant transformation of lymphocytes.

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TCRβ Feedback Signals Inhibit the Coupling of Recombinationally Accessible Vβ14 Segments with DJβ Complexes

Cited by 18 publications

References 74 publications

Regulation of TCRβ Allelic Exclusion by Gene Segment Proximity and Accessibility

Regulation of TCRβ Allelic Exclusion by Gene Segment Proximity and Accessibility

DNA Double-Strand Breaks Relieve USF-Mediated Repression of Dβ2 Germline Transcription in Developing Thymocytes

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

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