DNA ligase I is required for fetal liver erythropoiesis but is not essential for mammalian cell viability.
Four distinct DNA ligase activities (I-IV) have been identified within mammalian cells. Evidence has indicated that DNA ligase I is central to DNA replication, as well as being involved in DNA repair processes. A patient with altered DNA ligase I displayed a phenotype similar to Bloom's syndrome, being immunodeficient, growth retarded and predisposed to cancer. Fibroblasts isolated from this patient (46BR) exhibited abnormal lagging strand synthesis and repair deficiency. It has been reported that DNA ligase I is essential for cell viability, but here we show that cells lacking DNA ligase I are in fact viable. Using gene targeting in embryonic stem (ES) cells, we have produced DNA ligase I-deficient mice. Embryos develop normally to mid-term when haematopoiesis usually switches to the fetal liver. Thereupon acute anaemia develops, despite the presence of erythroid-committed progenitor cells in the liver. Thus DNA ligase I is required for normal development, but is not essential for replication. Hence a previously unsuspected redundancy must exist between mammalian DNA ligases.
Bentley
D
D
Institute of Cell and Molecular Biology, University of Edinburgh, UK.
Selfridge
J
J
Millar
J K
JK
Samuel
K
K
Hole
N
N
Ansell
J D
JD
Melton
D W
DW
D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000502:physiology*; D004920:Erythropoiesis; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D008099:Liver / Q000196:embryology* / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics
D012333:RNA, Messenger; D011088:DNA Ligases; D000072481:DNA Ligase ATP