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Autor(en): Rommel, Philipp Christian
Titel: RAG1/2 induces genomic insertions by mobilizing DNA into RAG1/2-independent breaks
Sonstige Titel: RAG1/2 induziert genomische Insertionen durch die Mobilisierung von DNA in RAG1/2-unabhängige Brüche
Erscheinungsdatum: 2017
Dokumentart: Dissertation
Seiten: 86
URI: http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-91180
http://elib.uni-stuttgart.de/handle/11682/9118
http://dx.doi.org/10.18419/opus-9101
Zusammenfassung: The RAG recombinase (RAG1/2) plays an essential role in adaptive immunity by mediating V(D)J recombination in developing lymphocytes. In contrast, aberrant RAG1/2 activity promotes lymphocyte malignancies by causing chromosomal translocations and DNA deletions at cancer genes. In addition, RAG1/2 can induce aberrant DNA insertions by transposition and trans-V(D)J recombination, but only few putative such events have been documented in vivo. Moreover, those observed in cancer display characteristics that are not compatible with either DNA transposition or trans-V(D)J recombination. Hence, how RAG1/2 causes genomic DNA insertions is still largely unknown. In this study, I use translocation capture sequencing (TC-Seq) and insertion capture sequencing (IC-Seq) to analyze chromosomal rearrangements in primary murine developing B cells. I identify aberrant RAG1/2-dependent DNA deletions at immunoglobulin genes, whose products are re-inserted at DNA breaks generated by the I-SceI endonuclease on a heterologous chromosome. The existence of similar insertions in human cancer indicates that RAG1/2 also mobilizes genomic DNA into independent physiologic breaks in vivo. Thus, my findings reveal a novel pathway through which RAG1/2 causes DNA insertions independent of DNA transposition and trans-V(D)J recombination. Importantly, this pathway has the potential to destabilize the lymphocyte genome by causing aberrant signal-end, hybrid-end and coding-end insertions and shares features with reported oncogenic DNA insertions.
Enthalten in den Sammlungen:04 Fakultät Energie-, Verfahrens- und Biotechnik

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