PUBLICATION

TopBP1 Governs Hematopoietic Stem/Progenitor Cells Survival in Zebrafish Definitive Hematopoiesis

Authors
Gao, L., Li, D., Ma, K., Zhang, W., Xu, T., Fu, C., Jing, C., Jia, X., Wu, S., Sun, X., Dong, M., Deng, M., Chen, Y., Zhu, W., Peng, J., Wan, F., Zhou, Y., Zon, L.I., Pan, W.
ID
ZDB-PUB-150702-5
Date
2015
Source
PLoS Genetics   11: e1005346 (Journal)
Registered Authors
Chen, Yi, Deng, Min, Dong, Mei, Jing, Chang-Bin, Pan, Weijun, Peng, Jinrong, Zhou, Yi, Zon, Leonard I.
Keywords
Embryos, Hematopoiesis, Zebrafish, DNA replication, DNA damage, Apoptosis, Immunostaining, Nonsense mutation
MeSH Terms
  • Carrier Proteins/genetics*
  • Carrier Proteins/metabolism
  • DNA Repair/genetics*
  • Cell Survival/genetics*
  • Codon, Nonsense/genetics
  • Hematopoietic Stem Cells/cytology*
  • Hematopoietic Stem Cells/metabolism
  • Checkpoint Kinase 1
  • Ataxia Telangiectasia Mutated Proteins
  • Embryo, Nonmammalian/metabolism
  • Cell Movement/genetics
  • DNA Damage/genetics
  • DNA Replication/genetics
  • DNA-Binding Proteins/metabolism
  • Hydroxyurea/pharmacology
  • DNA Topoisomerases, Type II/metabolism
  • Enzyme Activation/genetics
  • Hematopoiesis/genetics*
  • Animals
  • Apoptosis/physiology
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Protein Kinases/metabolism
  • Tumor Suppressor Protein p53/metabolism
  • Cell Proliferation
  • Zebrafish
(all 26)
PubMed
26131719 Full text @ PLoS Genet.
Abstract
In vertebrate definitive hematopoiesis, nascent hematopoietic stem/progenitor cells (HSPCs) migrate to and reside in proliferative hematopoietic microenvironment for transitory expansion. In this process, well-established DNA damage response pathways are vital to resolve the replication stress, which is deleterious for genome stability and cell survival. However, the detailed mechanism on the response and repair of the replication stress-induced DNA damage during hematopoietic progenitor expansion remains elusive. Here we report that a novel zebrafish mutantcas003 with nonsense mutation in topbp1 gene encoding topoisomerase II β binding protein 1 (TopBP1) exhibits severe definitive hematopoiesis failure. Homozygous topbp1cas003 mutants manifest reduced number of HSPCs during definitive hematopoietic cell expansion, without affecting the formation and migration of HSPCs. Moreover, HSPCs in the caudal hematopoietic tissue (an equivalent of the fetal liver in mammals) in topbp1cas003 mutant embryos are more sensitive to hydroxyurea (HU) treatment. Mechanistically, subcellular mislocalization of TopBP1cas003 protein results in ATR/Chk1 activation failure and DNA damage accumulation in HSPCs, and eventually induces the p53-dependent apoptosis of HSPCs. Collectively, this study demonstrates a novel and vital role of TopBP1 in the maintenance of HSPCs genome integrity and survival during hematopoietic progenitor expansion.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
No data available
Sequence Targeting Reagents
Fish
Antibodies
Orthology
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Engineered Foreign Genes
Marker Marker Type Name
EGFPEFGEGFP
1 - 1 of 1
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