RAG1/2 induces genomic insertions by mobilizing DNA into RAG1/2-independent breaks.

Autor:	Rommel PC; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065., Oliveira TY; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065., Nussenzweig MC; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 drobbiani@rockefeller.edu nussen@rockefeller.edu.; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065., Robbiani DF; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 drobbiani@rockefeller.edu nussen@rockefeller.edu.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2017 Mar 06; Vol. 214 (3), pp. 815-831. Date of Electronic Publication: 2017 Feb 08.
DOI:	10.1084/jem.20161638
Abstrakt:	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. RAG1/2 can also induce genomic DNA insertions by transposition and trans-V(D)J recombination, but only few such putative events have been documented in vivo. We used next-generation sequencing techniques to examine chromosomal rearrangements in primary murine B cells and discovered that RAG1/2 causes aberrant insertions by releasing cleaved antibody gene fragments that subsequently reintegrate into DNA breaks induced on a heterologous chromosome. We confirmed that RAG1/2 also mobilizes genomic DNA into independent physiological breaks by identifying similar insertions in human lymphoma and leukemia. Our findings reveal a novel RAG1/2-mediated insertion pathway distinct from DNA transposition and trans-V(D)J recombination that destabilizes the genome and shares features with reported oncogenic DNA insertions. (© 2017 Rommel et al.)
Databáze:	MEDLINE
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