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V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Here, we show that the genomic DNA that is excised during recombination, the excised signal circle (ESC), forms a complex with the recombinase proteins to efficiently catalyze breaks at single RSSs both in vitro and in vivo. Following cutting, the RSS is released while the ESC-recombinase complex remains intact to potentially trigger breaks at further RSSs. Consistent with this, chromosome breaks at RSSs increase markedly in the presence of the ESC. Notably, these breaks co-localize with those found in acute lymphoblastic leukemia patients and occur at key cancer driver genes. We have named this reaction "cut-and-run" and suggest that it could be a significant cause of lymphocyte genome instability. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.


Christopher M Kirkham, James N F Scott, Xiaoling Wang, Alastair L Smith, Adam P Kupinski, Anthony M Ford, David R Westhead, Peter G Stockley, Roman Tuma, Joan Boyes. Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability. Molecular cell. 2019 May 02;74(3):584-597.e9

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PMID: 30905508

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