DNA ligase I is required for fetal liver erythropoiesis but is not essential for mammalian cell viability

Abstract

Four distinct DMA ligase activities (I-IV) have been identified within mammalian cells^1–3. Evidence has indicated that DNA ligase I is central to DMA replication^4–7, as well as being involved in DNA repair processes^8,9. A patient with altered DNA ligase I displayed a phenotype similar to Bloom's syndrome, being immunodeficient, growth retarded and predisposed to cancer¹⁰. Fibroblasts isolated from this patient (46BR) exhibited abnormal lagging strand synthesis^11,12 and repair deficiency^13–15. It has been reported that DNA ligase I is essential for cell viability¹⁶, 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 l-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.