Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality

Silvia Alvarez; Marcos Díaz; Johanna Flach; Sara Rodriguez-Acebes; Andrés J López-Contreras; Dolores Martínez; Marta Cañamero; Oscar Fernández-Capetillo; Joan Isern; Emmanuelle Passegué; Juan Méndez

doi:10.1038/ncomms9548

Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality

Silvia Alvarez, Marcos Díaz, Johanna Flach, Sara Rodriguez-Acebes, Andrés J López-Contreras, Dolores Martínez, Marta Cañamero, Oscar Fernández-Capetillo, Joan Isern, Emmanuelle Passegué, Juan Méndez

53 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Nature Communications
Volume	6
Pages (from-to)	8548
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms9548
Publication status	Published - 12 Oct 2015
Externally published	Yes

Keywords

Animals
Checkpoint Kinase 1
DNA Damage
DNA Replication
Disease Susceptibility
Embryo, Mammalian
Embryonic Development
Erythropoiesis
Female
Genes, Lethal
Hematologic Neoplasms
Hematopoietic Stem Cells
Liver
Male
Mice, Inbred C57BL
Mice, Knockout
Minichromosome Maintenance Complex Component 3
Protein Kinases
Journal Article
Research Support, N.I.H., Extramural

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Alvarez, S., Díaz, M., Flach, J., Rodriguez-Acebes, S., López-Contreras, A. J., Martínez, D., Cañamero, M., Fernández-Capetillo, O., Isern, J., Passegué, E., & Méndez, J. (2015). Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality. Nature Communications, 6, 8548. https://doi.org/10.1038/ncomms9548

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abstract = "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.",

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AU - Alvarez, Silvia

AU - Díaz, Marcos

AU - Flach, Johanna

AU - Rodriguez-Acebes, Sara

AU - López-Contreras, Andrés J

AU - Martínez, Dolores

AU - Cañamero, Marta

AU - Fernández-Capetillo, Oscar

AU - Isern, Joan

AU - Passegué, Emmanuelle

AU - Méndez, Juan

PY - 2015/10/12

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N2 - 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.

AB - 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.

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KW - DNA Damage

KW - DNA Replication

KW - Disease Susceptibility

KW - Embryo, Mammalian

KW - Embryonic Development

KW - Erythropoiesis

KW - Female

KW - Genes, Lethal

KW - Hematologic Neoplasms

KW - Hematopoietic Stem Cells

KW - Liver

KW - Male

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Minichromosome Maintenance Complex Component 3

KW - Protein Kinases

KW - Journal Article

KW - Research Support, N.I.H., Extramural

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DO - 10.1038/ncomms9548

M3 - Journal article

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SN - 2041-1723

VL - 6

SP - 8548

JO - Nature Communications

JF - Nature Communications

ER -

Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality

Abstract

Keywords

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