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


The rapidly proliferating hematopoietic stem/progenitor cells (HSPCs) require well-established DNA damage response/repair pathways to resolve the DNA replication stress-induced DNA damage, which is deleterious for the genome stability and cell survival. Impairment of these pathways could lead to the progressive bone marrow failure (BMF) and hematopoietic malignancies. Here we reported a novel function of topoisomerase II β binding protein 1 (TopBP1) in definitive hematopoiesis through characterizing zebrafish mutantcas003 with a nonsense mutation in topbp1 gene encoding TopBP1. The homozygous topbp1 mutants manifested decreased HSPCs during their pool expansion in the caudal hematopoietic tissue (CHT, an equivalent of the fetal liver in mammals) due to the p53-dependent apoptosis. Further investigation revealed that the deficient TopBP1-ATR-Chk1 pathway upon DNA replication stress in topbp1 mutants led to accumulated DNA damage and further affected HSPCs survival. These studies therefore emphasized the importance of topbp1 function as well as DNA damage response pathways during the fetal HSPC rapid proliferation.


Vyšlo v časopise: TopBP1 Governs Hematopoietic Stem/Progenitor Cells Survival in Zebrafish Definitive Hematopoiesis. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005346
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005346

Souhrn

The rapidly proliferating hematopoietic stem/progenitor cells (HSPCs) require well-established DNA damage response/repair pathways to resolve the DNA replication stress-induced DNA damage, which is deleterious for the genome stability and cell survival. Impairment of these pathways could lead to the progressive bone marrow failure (BMF) and hematopoietic malignancies. Here we reported a novel function of topoisomerase II β binding protein 1 (TopBP1) in definitive hematopoiesis through characterizing zebrafish mutantcas003 with a nonsense mutation in topbp1 gene encoding TopBP1. The homozygous topbp1 mutants manifested decreased HSPCs during their pool expansion in the caudal hematopoietic tissue (CHT, an equivalent of the fetal liver in mammals) due to the p53-dependent apoptosis. Further investigation revealed that the deficient TopBP1-ATR-Chk1 pathway upon DNA replication stress in topbp1 mutants led to accumulated DNA damage and further affected HSPCs survival. These studies therefore emphasized the importance of topbp1 function as well as DNA damage response pathways during the fetal HSPC rapid proliferation.


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