Nucleic Acids Research Advance Access published online on August 23, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm579
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Nucleic Acid Enzymes |
Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence
1Departments of Pathology, Biochemistry & Molecular Biology, Biological Sciences, and Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA and 2Institute for Clinical Transfusion Medicine and Immunogenetics, Ulm, Department of Transfusion Medicine, University of Ulm, Ulm, Germany
*To whom correspondence should be addressed. Tel: +323 865 0568; Fax: +323 865 3019; Email: lieber{at}usc.edu
Correspondence may also be addressed to Klaus Schwarz. Tel: +49 731 150 642; Fax: +49 731 150 575; Email: klaus.schwarz{at}medizin.uni-ulm.de
Received June 12, 2007. Revised July 6, 2007. Accepted July 15, 2007.
The double-strand DNA break repair pathway, non-homologous DNA end joining (NHEJ), is distinctive for the flexibility of its nuclease, polymerase and ligase activities. Here we find that the joining of ends by XRCC4-ligase IV is markedly influenced by the terminal sequence, and a steric hindrance model can account for this. XLF (Cernunnos) stimulates the joining of both incompatible DNA ends and compatible DNA ends at physiologic concentrations of Mg2+, but only of incompatible DNA ends at higher concentrations of Mg2+, suggesting charge neutralization between the two DNA ends within the ligase complex. XRCC4-DNA ligase IV has the distinctive ability to ligate poly-dT single-stranded DNA and long dT overhangs in a Ku- and XLF-independent manner, but not other homopolymeric DNA. The dT preference of the ligase is interesting given the sequence bias of the NHEJ polymerase. These distinctive properties of the XRCC4-DNA ligase IV complex explain important aspects of its in vivo roles.
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