Journal of Biological Chemistry
Volume 286, Issue 39, 30 September 2011, Pages 33845-33853
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Cell Biology
Human Mre11/Human Rad50/Nbs1 and DNA Ligase IIIα/XRCC1 Protein Complexes Act Together in an Alternative Nonhomologous End Joining Pathway*

https://doi.org/10.1074/jbc.M111.274159Get rights and content
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Recent studies have implicated a poorly defined alternative pathway of nonhomologous end joining (alt-NHEJ) in the generation of large deletions and chromosomal translocations that are frequently observed in cancer cells. Here, we describe an interaction between two factors, hMre11/hRad50/Nbs1 (MRN) and DNA ligase IIIα/XRCC1, that have been linked with alt-NHEJ. Expression of DNA ligase IIIα and the association between MRN and DNA ligase IIIα/XRCC1 are altered in cell lines defective in the major NHEJ pathway. Most notably, DNA damage induced the association of these factors in DNA ligase IV-deficient cells. MRN interacts with DNA ligase IIIα/XRCC1, stimulating intermolecular ligation, and together these proteins join incompatible DNA ends in a reaction that mimics alt-NHEJ. Thus, our results provide novel mechanistic insights into the alt-NHEJ pathway that not only contributes to genome instability in cancer cells but may also be a therapeutic target.

Cancer
DNA Damage
DNA Enzymes
DNA Repair
Protein-Protein Interactions
DNA Double-strand Break
DNA Ligase III
Alternative Nonhomologous End Joining
Microhomology

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*

This work was supported, in whole or in part, by National Institutes of Health (NIH) Grant ES012512 from the NIEHS (to A. E. T.), NIH Program Project Grant CA92584 from the NCI (to A. E. T. and T. T. P.), and NIH Grant CA094008 (to T. T. P.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

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Present address: Battelle, Edgewood Chemical Biological Center, AMSRD-ECB-RT-BM, Bldg. E3831, 5183 Blackhawk Rd., Aberdeen Proving Ground, MD 21010.