Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta, and IV reveal direct DNA sensing ability and differential physiological functions in DNA repair Page: 3 of 29
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DNA ligases catalyze a common step in DNA replication, genetic recombination and DNA
repair. Consequently, defects in DNA ligation can cause cell lethality, increased genomic
instability and hypersensitivity to DNA damage . The DNA ligation reaction has three distinct
catalytic steps and involves covalent reaction intermediates. In eukaryotes, DNA ligases react
with ATP to form a covalent enzyme-adenylate intermediate. This first step occurs
independently of DNA whereas the subsequent two steps involve interactions between the DNA
ligase and its DNA substrate. In the second step, the AMP moiety is transferred to the 5'
phosphate terminus at a strand break to generate a covalent DNA adenylate intermediate.
Finally, the non-adenylated DNA ligase catalyzes phosphodiester bond formation in a reaction
that involves nucleophilic attack by the -OH group at the 3' terminus on the activated 5' DNA
adenylate and the release of AMP .
There are three human genes that encode DNA ligases, LIG1, LIG3 and LIG4 . Unlike
the LIG1 and LIG4 genes which encode a single DNA ligase polypeptide, the LIG3 gene
encodes nuclear and mitochondrial versions of DNA ligase lIla by alternative translation
initiation and a germ cell-specific version, DNA ligase lIP, by alternative splicing [2,3]. Mutations
in the LIG1 and LIG4 genes have been identified in humans and have been linked to cancer
predisposition and immunodeficiency [4-6]. Although no examples of human LIG3 mutations
have been observed, mutations in the genes encoding two proteins that associate with DNA
ligase Illa have been linked with neurodegenerative diseases, suggesting that DNA ligase Illa-
dependent repair pathways are critical in terminally differentiated neuronal cells [7,8].
The human DNA ligase polypeptides contain a conserved catalytic domain that is
flanked by different sequences that target these enzymes to various DNA metabolic pathways
. Both nuclear DNA ligase lIla and DNA ligase IV have a partner protein, XRCC1 and XRCC4
respectively, that is necessary for the stability and activity of the DNA ligase in vivo [9,10]. A
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Chen, Xi; Ballin, Jeff D.; Della-Maria, Julie; Tsai, Miaw-Sheue; White, Elizabeth J.; Tomkinson, Alan E. et al. Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta, and IV reveal direct DNA sensing ability and differential physiological functions in DNA repair, article, May 11, 2009; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc926316/m1/3/: accessed November 20, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.