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DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability

¹ Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh EH9 3JR, UK
² Sir Alastair Currie CRC Laboratories, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, UK
³ Cell Therapy Group, Scottish National Blood Transfusion Service, Edinburgh EH4 2XU, UK
⁴ John Hughes Bennett Laboratory, Department of Oncology, University of Edinburgh, Edinburgh EH4 2XU, UK

^* Author for correspondence (e-mail: David.Melton{at}ed.ac.uk

Accepted 6 January 2002

DNA ligase I is the key ligase for DNA replication in mammalian cells and has also been reported to be involved in a number of recombination and repair processes. Our previous finding that Lig1 knockout mouse embryos developed normally to mid-term before succumbing to a specific haematopoietic defect was difficult to reconcile with a report that DNA ligase I is essential for the viability of cultured mammalian cells. To address this issue, we generated a second Lig1 targeted allele and found that the phenotypes of our two Lig1 mutant mouse lines are identical. Widely different levels of Lig1 fusion transcripts were detected from the two targeted alleles, but we could not detect any DNA ligase I protein, and we believe both are effective Lig1 null alleles. Using foetal liver cells to repopulate the haematopoietic system of lethally irradiated adult mice, we demonstrate that the haematopoietic defect in DNA-ligase-I-deficient embryos is a quantitative deficiency relating to reduced proliferation rather than a qualitative block in any haematopoietic lineage. DNA ligase I null fibroblasts from Lig1 mutant embryos showed an accumulation of DNA replication intermediates and increased genome instability. In the absence of a demonstrable deficiency in DNA repair we postulate that, unusually, genome instability may result directly from the DNA replication defect. Lig1 null mouse cells performed better in the survival and replication assays than a human LIG1 point mutant, and we suggest that the complete absence of DNA ligase I may make it easier for another ligase to compensate for DNA ligase I deficiency.

Key words: DNA ligases, DNA repair, DNA replication, Genome instability

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