Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability.
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Date
2019-05-02ICR Author
Author
Kirkham, CM
Scott, JNF
Wang, X
Smith, AL
Kupinski, AP
Ford, AM
Westhead, DR
Stockley, PG
Tuma, R
Boyes, J
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
COS Cells
NIH 3T3 Cells
Chromosomes
Animals
Humans
Mice
Translocation, Genetic
Genomic Instability
Recombinases
Homeodomain Proteins
DNA
Base Sequence
DNA Breaks, Double-Stranded
Precursor Cell Lymphoblastic Leukemia-Lymphoma
HEK293 Cells
V(D)J Recombination
Chlorocebus aethiops
Research team
Biology of Childhood Leukaemia
Language
eng
Date accepted
2019-02-14
License start date
2019-05
Citation
Molecular cell, 2019, 74 (3), pp. 584 - 597.e9
Publisher
CELL PRESS