Genetic and epigenetic determinants mediate proneness of oncogene breakpoint sites for involvement in TCR translocations
| Autor: | Nicole S. D. Larmonie, A van der Spek, Anthonie Willem Langerak, J. J. M. Van Dongen, Ad J.J.C. Bogers |
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| Přispěvatelé: | Immunology, Cardiothoracic Surgery |
| Rok vydání: | 2014 |
| Předmět: |
Immunology
Receptors Antigen T-Cell Translocation Breakpoint Context (language use) Chromosomal translocation Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Translocation Genetic Epigenesis Genetic Chromosome Breakpoints Proto-Oncogene Proteins Basic Helix-Loop-Helix Transcription Factors Genetics Humans Recombination signal sequences DNA Breaks Double-Stranded Epigenetics Child T-Cell Acute Lymphocytic Leukemia Protein 1 Genetics (clinical) Adaptor Proteins Signal Transducing Homeodomain Proteins Thymocytes Base Sequence Breakpoint T-cell receptor Infant Newborn Infant Sequence Analysis DNA DNA Methylation LIM Domain Proteins V(D)J Recombination Chromatin Child Preschool Proto-Oncogene Proteins c-bcr |
| Zdroj: | Genes and Immunity, 15(2), 72-81. Nature Publishing Group |
| ISSN: | 1476-5470 1466-4879 |
| Popis: | T-cell receptor (TCR) translocations are a genetic hallmark of T-cell acute lymphoblastic leukemia and lead to juxtaposition of oncogene and TCR loci. Oncogene loci become involved in translocations because they are accessible to the V(D)J recombination machinery. Such accessibility is predicted at cryptic recombination signal sequence (cRSS) sites ('Type 1') as well as other sites that are subject to DNA double-strand breaks (DSBs) ('Type 2') during early stages of thymocyte development. As chromatin accessibility markers have not been analyzed in the context of TCR-associated translocations, various genetic and epigenetic determinants of LMO2, TAL1 and TLX1 translocation breakpoint (BP) sites and BP cluster regions (BCRs) were examined in human thymocytes to establish DSB proneness and heterogeneity of BP site involvement in TCR translocations. Our data show that DSBs in BCRs are primarily induced in the presence of a genetic element of sequence vulnerability (cRSSs, transposable elements), whereas breaks at single BP sites lacking such elements are more likely induced by chance or perhaps because of patient-specific genetic vulnerability. Vulnerability to obtain DSBs is increased by features that determine chromatin organization, such as methylation status and nucleosome occupancy, although at different levels at different BP sites. |
| Databáze: | OpenAIRE |
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