Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability.
Mol Cell
; 74(3): 584-597.e9, 2019 05 02.
Article
en En
| MEDLINE
| ID: mdl-30905508
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Translocación Genética
/
Inestabilidad Genómica
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Recombinación V(D)J
Tipo de estudio:
Etiology_studies
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2019
Tipo del documento:
Article