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J. Biol. Chem., Vol. 283, Issue 1, 1-5, January 4, 2008

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Minireview

The Mechanism of Human Nonhomologous DNA End Joining^*

From the Norris Comprehensive Cancer Center, Departments of Pathology, Biochemistry and Molecular Biology, Molecular Microbiology and Immunology, and Biological Sciences, University of Southern California Keck School of Medicine, Los Angeles, California 90089-9176

Double-strand breaks are common in all living cells, and there are two major pathways for their repair. In eukaryotes, homologous recombination is restricted to late S or G₂, whereas nonhomologous DNA end joining (NHEJ) can occur throughout the cell cycle and is the major pathway for the repair of double-strand breaks in multicellular eukaryotes. NHEJ is distinctive for the flexibility of the nuclease, polymerase, and ligase activities that are used. This flexibility permits NHEJ to function on the wide range of possible substrate configurations that can arise when double-strand breaks occur, particularly at sites of oxidative damage or ionizing radiation. NHEJ does not return the local DNA to its original sequence, thus accounting for the wide range of end results. Part of this heterogeneity arises from the diversity of the DNA ends, but much of it arises from the many alternative ways in which the nuclease, polymerases, and ligase can act during NHEJ. Physiologic double-strand break processes make use of the imprecision of NHEJ in generating antigen receptor diversity. Pathologically, the imprecision of NHEJ contributes to genome mutations that arise over time.

^* This minireview will be reprinted in the 2008 Minireview Compendium, which will be available in January, 2009.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–6 and Refs. 1–3.

¹ To whom correspondence should be addressed: USC Keck School of Medicine, Rm. 5428, 1441 Eastlake Ave., MC9176, Los Angeles, CA 90089-9176. Tel.: 323-865-0568; Fax: 323-865-3019; E-mail: lieber{at}usc.edu.

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