2026-06-14T03:30:03Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/53852024-11-29T16:37:45Zcom_20.500.12105_19604com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_19605col_20.500.12105_19597
Repisalud
author
Alvarez, Silvia
author
Diaz, Marcos
author
Flach, Johanna
author
Rodriguez-Acebes, Sara
author
Lopez-Contreras, Andres J.
author
Martinez, Dolores
author
Cañamero, Marta
author
Fernandez-Capetillo, Oscar
author
Isern, Joan
author
Passegue, Emmanuelle
author
Mendez, Juan
funder
Ministerio de Economía y Competitividad (España)
funder
European Molecular Biology Organization
2017-11-27T13:49:49Z
2017-11-27T13:49:49Z
2015
Nat Commun. 2015; 6:8548
10.1038/ncomms9548
2041-1723
Nature Communications
26456157
http://hdl.handle.net/20.500.12105/5385
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.
eng
DNA-REPLICATION
DORMANT ORIGINS
EXCESS MCM2-7
IN-VIVO
DAMAGE
CYCLE
CANCER
LOCUS
DIFFERENTIATION
SPECIFICATION
Replication stress caused by low MCM expression limits fetal
erythropoiesis and hematopoietic stem cell functionality
journal article
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