Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Anhydride Hydrolases
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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DNA Damage / physiology
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DNA Ligase ATP
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DNA Ligases / genetics
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DNA Ligases / metabolism*
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DNA Repair / physiology*
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DNA Repair Enzymes / genetics
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DNA Repair Enzymes / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Genomic Instability / physiology
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Humans
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MRE11 Homologue Protein
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Poly-ADP-Ribose Binding Proteins
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X-ray Repair Cross Complementing Protein 1
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Xenopus Proteins
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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MRE11 protein, human
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Multiprotein Complexes
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NBN protein, human
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Nuclear Proteins
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Poly-ADP-Ribose Binding Proteins
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X-ray Repair Cross Complementing Protein 1
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XRCC1 protein, human
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Xenopus Proteins
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MRE11 Homologue Protein
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Acid Anhydride Hydrolases
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RAD50 protein, human
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DNA Ligases
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DNA Repair Enzymes
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DNA Ligase ATP
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DNA ligase III alpha protein, Xenopus