title: Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia.
abstract: Diamond-Blackfan anaemia (DBA) is a cancer-prone genetic disorder characterized by pure red-cell aplasia and associated physical deformities. The ribosomal protein S19 gene (RPS19) is the most frequently mutated gene in DBA (~25%). TP53-mediated cell cycle arrest and/or apoptosis in erythroid cells have been suggested to be major factors for DBA development, but it is not clear why mutations in the ubiquitously expressed RPS19 gene specifically affect erythropoiesis. Previously, we showed that RPS19 deficiency in zebrafish recapitulates the erythropoietic and developmental phenotypes of DBA, including defective erythropoiesis with severe anaemia. In this study, we analysed the simultaneous loss-of-function of RPS19 and Tp53 in zebrafish to investigate the role of Tp53 in the erythroid and morphological defects associated with RPS19 deficiency. Co-inhibition of Tp53 activity rescued the morphological abnormalities, but did not alleviate erythroid aplasia in RPS19-deficient zebrafish. In addition, knockdown of two other RP genes, rps3a and rpl36a, which result in severe morphological abnormalities but only mild erythroid defects, also elicited an activated Tp53 response. These results suggest that a Tp53-independent but RPS19-dependent pathway could be responsible for defective erythropoiesis in RPS19-deficient zebrafish.
authors.affiliation: Frontier Science Research Centre, University of Miyazaki, Kiyotake, Miyazaki, Japan.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Torihara
authors.forename: Tamayo
authors.initials: T
authors.lastname: Uechi
authors.forename: Anirban
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Minori
authors.initials: M
authors.lastname: Shinya
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Sakai
authors.forename: Naoya
authors.initials: N
authors.lastname: Kenmochi
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000502:physiology*; D016158:Genes, p53; D012333:RNA, Messenger / Q000235:genetics; D012269:Ribosomal Proteins / Q000172:deficiency* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*; D015027:Zebrafish
chemical_list: D012333:RNA, Messenger; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C040343:ribosomal protein S19