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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.

Original publication

DOI

10.1016/j.molcel.2019.02.025

Type

Journal article

Journal

Mol Cell

Publication Date

02/05/2019

Volume

74

Pages

584 - 597.e9

Keywords

RAG proteins, V(D)J recombination, acute lymphoblastic leukemia, chromosome translocations, double strand breaks, genome instability, Animals, Base Sequence, COS Cells, Chlorocebus aethiops, Chromosomes, DNA, DNA Breaks, Double-Stranded, Genomic Instability, HEK293 Cells, Homeodomain Proteins, Humans, Mice, NIH 3T3 Cells, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Recombinases, Translocation, Genetic, V(D)J Recombination