Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta, and IV reveal direct DNA sensing ability and differential physiological functions in DNA repair Page: 2 of 29
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The three human LIG genes encode polypeptides that catalyze phosphodiester bond formation
during DNA replication, recombination and repair. While numerous studies have identified
protein partners of the human DNA ligases (hLigs), there has been little characterization of the
catalytic properties of these enzymes. In this study, we developed and optimized a
fluorescence-based DNA ligation assay to characterize the activities of purified hLigs. Although
hLigl joins DNA nicks, it has no detectable activity on linear duplex DNA substrates with short,
cohesive single-strand ends. By contrast, hLiglll and the hLigllla/XRCC1 and hLiglV/XRCC4
complexes are active on both nicked and linear duplex DNA substrates. Surprisingly,
hLiglV/XRCC4, which is a key component of the major non-homologous end joining (NHEJ)
pathway, is significantly less active than hLiglll on a linear duplex DNA substrate. Notably,
hLiglV/XRCC4 molecules only catalyze a single ligation event in the absence or presence of
ATP. The failure to catalyze subsequent ligation events reflects a defect in the enzyme-
adenylation step of the next ligation reaction and suggests that, unless there is an in vivo
mechanism to reactivate DNA ligase IV/XRCC4 following phosphodiester bond formation, the
cellular NHEJ capacity will be determined by the number of adenylated DNA ligaselV/XRCC4
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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/m1/2/: accessed January 17, 2019), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.