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Nucleic Acids Research Advance Access originally published online on April 24, 2008
Nucleic Acids Research 2008 36(10):3297-3310; doi:10.1093/nar/gkn184
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Nucleic Acids Research, 2008, Vol. 36, No. 10 3297-3310
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Human DNA ligases I and III, but not ligase IV, are required for microhomology-mediated end joining of DNA double-strand breaks

Li Liang*, Li Deng, Son C. Nguyen, Xin Zhao, Christopher D. Maulion, Changshun Shao and Jay A. Tischfield

Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA

*To whom correspondence should be addressed. Tel: +732 445 5406; Fax: +732 445 1147; Email: liang{at}biology.rutgers.edu

Received January 7, 2008. Revised March 24, 2008. Accepted March 31, 2008.

DNA nonhomologous end-joining (NHEJ) and homologous recombination are two distinct pathways of DNA double-strand break repair in mammalian cells. Biochemical and genetic studies showed that DNA ends can also be joined via microhomology-mediated end joining (MHEJ), especially when proteins responsible for NHEJ, such as Ku, are reduced or absent. While it has been known that Ku-dependent NHEJ requires DNA ligase IV, it is unclear which DNA ligase(s) is required for Ku-independent MHEJ. In this study, we used a cell-free assay to determine the roles of DNA ligases I, III and IV in MHEJ and NHEJ. We found that siRNA mediated down-regulation of DNA ligase I or ligase III in human HTD114 cells led to impaired end joining that was mediated by 2-, 3- or 10-bp microhomology. In addition, nuclear extract from human fibroblasts harboring a mutation in DNA ligase I displayed reduced MHEJ activity. Furthermore, treatment of HTD114 nuclear extracts with an antibody against DNA ligase I or III also significantly reduced MHEJ. These data indicate that DNA ligases I and III are required in MHEJ. DNA ligase IV, on the contrary, is not required in MHEJ but facilitates Ku-dependent NHEJ. Therefore, MHEJ and NHEJ require different DNA ligases.


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