View the Current Issue

Article

  • The EMBO Journal (2007) 26, 1010 - 1023
  • doi:10.1038/sj.emboj.7601559

Published online: 8 February 2007

XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps

Jiafeng Gu1,2, Haihui Lu1, Brigette Tippin2,a, Noriko Shimazaki1, Myron F Goodman2 and Michael R Lieber1,2

  1. Departments of Pathology, Biochemistry and Molecular Biology, Molecular Microbiology and Immunology, and Biological Sciences, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
  2. Department of Biological Sciences, Los Angeles, CA, USA

Correspondence to:

Michael R Lieber, Norris Cancer Ctr., Rm. 5428, University of Southern California, 1441 Eastlake Ave., MC 9176, Los Angeles, CA 90033, USA. Tel.: +1 323 865 0568; Fax: +1 323 865 3019; E-mail: lieber@usc.edu

aPresent address: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W Carson Street, Torrance, CA 90502, USA

Received 2 October 2006; Accepted 19 December 2006

XRCC4 and DNA ligase IV form a complex that is essential for the repair of all double-strand DNA breaks by the nonhomologous DNA end joining pathway in eukaryotes. We find here that human XRCC4:DNA ligase IV can ligate two double-strand DNA ends that have fully incompatible short 3' overhang configurations with no potential for base pairing. Moreover, at DNA ends that share 1–4 annealed base pairs, XRCC4:DNA ligase IV can ligate across gaps of 1 nt. Ku can stimulate the joining, but is not essential when there is some terminal annealing. Polymerase mu can add nucleotides in a template-independent manner under physiological conditions; and the subset of ends that thereby gain some terminal microhomology can then be ligated. Hence, annealing at sites of microhomology is very important, but the flexibility of the ligase complex is paramount in nonhomologous DNA end joining. These observations provide an explanation for several in vivo observations that were difficult to understand previously.

  • Keywords:

    • DNA repair,
    • DNA recombination,
    • immunoglobulin gene rearrangement,
    • NHEJ,
    • V(D)J recombination