Mycobacterial Ku and ligase proteins constitute a two-component NHEJ repair machine |
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Authors: | Della Marina Palmbos Phillip L Tseng Hui-Min Tonkin Louise M Daley James M Topper Leana M Pitcher Robert S Tomkinson Alan E Wilson Thomas E Doherty Aidan J |
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Affiliation: | Cambridge Institute for Medical Research, University of Cambridge, Department of Haematology, Hills Road, Cambridge CB2 2XY, UK. |
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Abstract: | In mammalian cells, repair of DNA double-strand breaks (DSBs) by nonhomologous end-joining (NHEJ) is critical for genome stability. Although the end-bridging and ligation steps of NHEJ have been reconstituted in vitro, little is known about the end-processing reactions that occur before ligation. Recently, functionally homologous end-bridging and ligation activities have been identified in prokarya. Consistent with its homology to polymerases and nucleases, we demonstrate that DNA ligase D from Mycobacterium tuberculosis (Mt-Lig) possesses a unique variety of nucleotidyl transferase activities, including gap-filling polymerase, terminal transferase, and primase, and is also a 3' to 5' exonuclease. These enzyme activities allow the Mt-Ku and Mt-Lig proteins to join incompatible DSB ends in vitro, as well as to reconstitute NHEJ in vivo in yeast. These results demonstrate that prokaryotic Ku and ligase form a bona fide NHEJ system that encodes all the recognition, processing, and ligation activities required for DSB repair. |
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