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

被引：79

作者：

Alvarez, Silvia ^{[1
]}

Diaz, Marcos ^{[1
]}

Flach, Johanna ^{[2
]}

Rodriguez-Acebes, Sara ^{[1
]}

Lopez-Contreras, Andres J. ^{[3
]}

Martinez, Dolores ^{[4
]}

Canamero, Marta ^{[5
]}

Fernandez-Capetillo, Oscar ^{[3
]}

Isern, Joan ^{[6
]}

Passegue, Emmanuelle ^{[2
]}

Mendez, Juan ^{[1
]}

机构：

[1] Spanish Natl Canc Res Ctr CNIO, DNA Replicat Grp, Madrid 28029, Spain

[2] UCSF, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA

[3] Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid 28029, Spain

[4] Spanish Natl Canc Res Ctr CNIO, Flow Cytometry Unit, Madrid 28029, Spain

[5] Spanish Natl Canc Res Ctr CNIO, Compared Pathol Unit, Madrid 28029, Spain

[6] Spanish Natl Cardiovascular Res Ctr CNIC, Madrid 28029, Spain

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

DNA-REPLICATION; DORMANT ORIGINS; EXCESS MCM2-7; DAMAGE; LOCUS; CYCLE; SPECIFICATION; EMBRYOGENESIS; DEFICIENCY; INITIATION;

D O I：

10.1038/ncomms9548

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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