Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/5385
Título
Replication stress caused by low MCM expression limits fetal
erythropoiesis and hematopoietic stem cell functionality
Autor(es)
Alvarez, Silvia | Diaz, Marcos | Flach, Johanna | Rodriguez-Acebes, Sara CNIO | Lopez-Contreras, Andres J. | Martinez, Dolores | Cañamero, Marta | Fernandez-Capetillo, Oscar CNIO | Isern, Joan CNIC | Passegue, Emmanuelle | Mendez, Juan CNIO
Fecha de publicación
2015
Cita
Nat Commun. 2015; 6:8548
Idioma
Inglés
Tipo de documento
journal article
Resumen
Replicative stress during embryonic development influences ageing and
predisposition to disease in adults. A protective mechanism against
replicative stress is provided by the licensing of thousands of origins
in G1 that are not necessarily activated in the subsequent S-phase.
These `dormant' origins provide a backup in the presence of stalled
forks and may confer flexibility to the replication program in specific
cell types during differentiation, a role that has remained unexplored.
Here we show, using a mouse strain with hypomorphic expression of the
origin licensing factor mini-chromosome maintenance (MCM)3 that limiting
origin licensing in vivo affects the functionality of hematopoietic stem
cells and the differentiation of rapidly-dividing erythrocyte
precursors. Mcm3-deficient erythroblasts display aberrant DNA
replication patterns and fail to complete maturation, causing lethal
anemia. Our results indicate that hematopoietic progenitors are
particularly sensitive to replication stress, and full origin licensing
ensures their correct differentiation and functionality.
Palabras clave
DNA-REPLICATION | DORMANT ORIGINS | EXCESS MCM2-7 | IN-VIVO | DAMAGE | CYCLE | CANCER | LOCUS | DIFFERENTIATION | SPECIFICATION
Versión en línea
DOI
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