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

Author:
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
Source:
Molecular cell 2019 v.74 no.3 pp. 584-597.e9
ISSN:
1097-2765
Subject:
DNA, DNA-binding proteins, antigens, chromosome breakage, chromosomes, cutting, enzymes, genes, lymphocytic leukemia, patients, signal peptide
Abstract:
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.
Agid:
6394667