title: Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality.
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.
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alvarez
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Díaz
authors.affiliation: The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, 94143 California, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Flach
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Rodriguez-Acebes
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Andrés J
authors.initials: AJ
authors.lastname: López-Contreras
authors.affiliation: Flow Cytometry Unit, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Martínez
authors.affiliation: Compared Pathology Unit, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández-Capetillo
authors.affiliation: Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Isern
authors.affiliation: The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, 94143 California, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Méndez
mesh_terms: D000818:Animals; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004261:DNA Replication; D004198:Disease Susceptibility; D004622:Embryo, Mammalian / Q000502:physiology; D047108:Embryonic Development; D004920:Erythropoiesis; D005260:Female; D005804:Genes, Lethal; D019337:Hematologic Neoplasms; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008099:Liver / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064126:Minichromosome Maintenance Complex Component 3 / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D064126:Minichromosome Maintenance Complex Component 3