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  • *DNA End-Joining Repair  (1)
  • Nature Publishing Group (NPG)  (1)
  • American Association for the Advancement of Science (AAAS)
  • Nature Publishing Group (NPG)  (1)
  • American Association for the Advancement of Science (AAAS)
  • 1
    Publication Date: 2015-02-03
    Description: The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions. Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Poltheta; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Poltheta has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mateos-Gomez, Pedro A -- Gong, Fade -- Nair, Nidhi -- Miller, Kyle M -- Lazzerini-Denchi, Eros -- Sfeir, Agnel -- AG038677/AG/NIA NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- R01 AG038677/AG/NIA NIH HHS/ -- England -- Nature. 2015 Feb 12;518(7538):254-7. doi: 10.1038/nature14157. Epub 2015 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU School of Medicine, New York, New York 10016, USA. ; Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin. 2506 Speedway Stop A5000, Austin, Texas 78712, USA. ; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Death/genetics ; Cell Line ; Chromosome Aberrations ; Chromosomes, Mammalian/genetics/*metabolism ; *DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; DNA-Directed DNA Polymerase/deficiency/*metabolism ; Genes, BRCA1 ; Genes, BRCA2 ; HeLa Cells ; Humans ; Mice ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Rad51 Recombinase/metabolism ; *Recombination, Genetic/genetics ; Recombinational DNA Repair/genetics ; Telomere/*genetics/*metabolism ; Translocation, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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