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 and Juan Méndez ()
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Silvia Alvarez: DNA Replication Group, Spanish National Cancer Research Centre (CNIO)
Marcos Díaz: DNA Replication Group, Spanish National Cancer Research Centre (CNIO)
Johanna Flach: The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, UCSF
Sara Rodriguez-Acebes: DNA Replication Group, Spanish National Cancer Research Centre (CNIO)
Andrés J. López-Contreras: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)
Dolores Martínez: Flow Cytometry Unit, Spanish National Cancer Research Centre (CNIO)
Marta Cañamero: Compared Pathology Unit, Spanish National Cancer Research Centre (CNIO)
Oscar Fernández-Capetillo: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)
Joan Isern: Spanish National Cardiovascular Research Center (CNIC)
Emmanuelle Passegué: The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, UCSF
Juan Méndez: DNA Replication Group, Spanish National Cancer Research Centre (CNIO)

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9548

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