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

Bentley, Darren; Selfridge, Jim; Millar, J. Kirsty; Samuel, Kay; Hole, Nicholas; Ansell, Jake; Melton, David W.

doi:10.1038/ng0896-489

Cited by 109 publications

(68 citation statements)

References 26 publications

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“…This notion was supported by the observation that loss of both LIG1 alleles in mouse embryonic stem cells was only observed in cells ectopically expressing full-length DNA ligase I cDNA (56). Thus, it was surprising that mouse embryos harboring homozygous deletions of the 3′ end of the LIG1 gene developed normally until midgestation (57). It is possible that the embryos were not totally devoid of DNA ligase I activity because the gene-targeting strategy did not disrupt the LIG1 gene by deleting the first exon.…”

Section: Dna Ligase I Familysupporting

confidence: 52%

“…As expected, MEFs established from these animals are defective in Okazaki fragment joining (59). Unlike the 46BR.1G1-immortalized human fibroblast cell line, neither these MEFs nor the MEFs established from the lig1 null mice are sensitive to DNA-damaging agents, including DNA-alkylating agents (57)(58)(59). It is possible that differences in the relative contribution of the short-and long-patch sub-pathways of base excision repair (BER) underlie the different DNA damage sensitivities of human and mouse cell lines expressing the same mutant version of DNA ligase I.…”

Section: Dna Ligase I Familymentioning

confidence: 99%

“…However, a similar result was obtained using a different targeting strategy (although again not targeting the first exon) (58). Mouse embryonic fibroblast (MEF) cell lines established from both of these animal models proliferate normally but have a defect in Okazaki fragment joining and increased genomic instability (57,58). Thus, there is strong evidence that mammalian DNA ligase I is not absolutely required for DNA replication and for the early stages of embryo development.…”

Section: Dna Ligase I Familymentioning

confidence: 99%

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Eukaryotic DNA Ligases: Structural and Functional Insights

Ellenberger

Tomkinson

2008

Annu. Rev. Biochem.

291

338

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DNA ligases are required for DNA replication, repair, and recombination. In eukaryotes, there are three families of ATP-dependent DNA ligases. Members of the DNA ligase I and IV families are found in all eukaryotes, whereas DNA ligase III family members are restricted to vertebrates. These enzymes share a common catalytic region comprising a DNA-binding domain, a nucleotidyltransferase (NTase) domain, and an oligonucleotide/oligosaccharide binding (OB)-fold domain. The catalytic region encircles nicked DNA with each of the domains contacting the DNA duplex. The unique segments adjacent to the catalytic region of eukaryotic DNA ligases are involved in specific protein-protein interactions with a growing number of DNA replication and repair proteins. These interactions determine the specific cellular functions of the DNA ligase isozymes. In mammals, defects in DNA ligation have been linked with an increased incidence of cancer and neurodegeneration.

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Section: Dna Ligase I Familysupporting

confidence: 52%

Section: Dna Ligase I Familymentioning

confidence: 99%

Section: Dna Ligase I Familymentioning

confidence: 99%

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Eukaryotic DNA Ligases: Structural and Functional Insights

Ellenberger

Tomkinson

2008

Annu. Rev. Biochem.

291

338

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“…However, in apparent conflict with these data, DNA ligase I null mouse embryos survived into midterm before dying of acute anemia (28). In this latter study, only the final four exons out of a total of 28 in the mouse DNA ligase I gene were deleted.…”

Section: Discussionmentioning

confidence: 39%

Specific Function of DNA Ligase I in Simian Virus 40 DNA Replication by Human Cell-free Extracts Is Mediated by the Amino-terminal Non-catalytic Domain

Mackenney¹,

Barnes²,

Lindahl³

1997

Journal of Biological Chemistry

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The joining of Okazaki fragments during lagging strand DNA replication in mammalian cells is believed to be due to DNA ligase I. This enzyme is composed of a 78-kDa carboxyl-terminal catalytic domain and a 24-kDa amino-terminal region that is not required for ligation activity in vitro. Extracts of the human cell line 46BR.1G1, in which DNA ligase I is mutationally altered, supported aberrant in vitro SV40 DNA replication; the joining of Okazaki fragments was defective, and unligated intermediates were unstable. Human DNA ligase I, but not DNA ligase III or bacteriophage T4 DNA ligase, complemented both defects in 46BR.1G1 extracts. The catalytic domain of DNA ligase I was 10-fold less effective in complementation experiments than the fulllength protein, indicating that the amino-terminal region of the enzyme is required for efficient lagging strand DNA replication. Moreover, in vitro SV40 DNA replication in normal human cell extracts was inhibited by an excess of either full-length DNA ligase I or the amino-terminal region of the protein, but not by the catalytic domain. This inhibition may be mediated by the interaction of the amino-terminal region of DNA ligase I with other replication proteins.Several distinct DNA ligases have been identified in mammalian cells, DNA ligase I being a major activity in proliferating cells (1, 2). Cytostaining experiments with antibodies against DNA ligase I showed that the enzyme is specifically localized in the nucleus with the same granular staining pattern as DNA polymerase ␣, implicating DNA ligase I in DNA replication (3). DNA ligase I (in conjunction with DNA polymerase ␣, ␦, or ⑀; RNase H1; and the 5Ј-nuclease DNase IV/ FEN-1) is able to complete lagging strand DNA replication in vitro on a synthetic DNA substrate (4), and DNA ligase I activity also functions to generate closed circular DNA during SV40 DNA replication reconstituted with SV40 large T antigen and purified mammalian proteins (5, 6).The human DNA ligase I cDNA encodes a 102-kDa polypeptide (7). A 78-kDa carboxyl-terminal domain shows significant amino acid sequence homology to the CDC9 and cdc17 ϩ gene products of Saccharomyces cerevisiae and Schizosaccharomyces pombe as well as to the human DNA ligase III and IV cDNAs. This domain is catalytically active in vitro in the absence of the amino-terminal region and is able to complement a conditional/ lethal DNA ligase mutant of Escherichia coli (8). The 24-kDa amino-terminal portion of human DNA ligase I is a proteasesensitive hydrophilic region that has no counterpart in other mammalian DNA ligases or the yeast DNA ligases. Although this amino-terminal region is not required for activity of DNA ligase I in standard in vitro DNA joining assays, it is essential in vivo to counteract the lethal effect of knocking out DNA ligase I in mouse embryonic stem cells by the ectopic expression of DNA ligase I (9). A functional role for the amino-terminal portion of DNA ligase I during DNA replication has not been directly demonstrated, but this region may serve to locali...

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“…These observations indicate that Polb plays an important role in neural development. So far, some knockout mice defective in BER factors have been generated; mice deficient in FEN1, 11 APE, 12 XRCC1 13 and DNA ligase I (LigI) 14 are all embryonic lethal at E3.5-E16.5. These findings clearly indicate that BER plays critical roles in development.…”

Section: Introductionmentioning

confidence: 99%