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Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability

Kirkham, Christopher M., Scott, James N.F., Wang, Xiaoling, Smith, Alastair L., Kupinski, Adam P., Ford, Anthony M., Westhead, David R., Stockley, Peter G., Tuma, Roman, Boyes, Joan
Molecular cell 2019 v.74 no.3 pp. 584-597.e9
DNA, DNA-binding proteins, antigens, chromosome breakage, chromosomes, cutting, enzymes, genes, lymphocytic leukemia, patients, signal peptide
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.