Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction
| Autor: | Jacob Zimbric, Yongbao Wang, Eric A. Hendrickson, Sehyun Oh |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Genome instability
DNA End-Joining Repair DNA Ligases Chromatids Genome Integrity Repair and Replication Biology medicine.disease_cause Genomic Instability DNA Ligase ATP 03 medical and health sciences 0302 clinical medicine Telomere Homeostasis Cell Line Tumor Genetics medicine Humans Telomeric Repeat Binding Protein 2 Ku Autoantigen Cell Proliferation 030304 developmental biology Chromosome Aberrations Recombination Genetic 0303 health sciences Ku70 Mutation DNA Helicases Nuclear Proteins Recombinational DNA Repair Gene targeting Antigens Nuclear Telomere DNA-Binding Proteins 030220 oncology & carcinogenesis Gene Targeting Chromatid Homologous recombination DNA Damage |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | Classic non-homologous end joining (C-NHEJ) is the predominant DNA double-strand break repair pathway in humans. Although seven genes Ku70, Ku86, DNA-PK(cs), Artemis, DNA Ligase IV (LIGIV), X-ray cross-complementing group 4 and XRCC4-like factor are required for C-NHEJ, several of them also have ancillary functions. For example, Ku70:Ku86 possesses an essential telomere maintenance activity. In contrast, LIGIV is believed to function exclusively in C-NHEJ. Moreover, a viable LIGIV-null human B-cell line and LIGIV-reduced patient cell lines have been described. Together, these observations suggest that LIGIV (and hence C-NHEJ), albeit important, is nonetheless dispensable, whereas Ku70:Ku86 and telomere maintenance are essential. To confirm this hypothesis, we inactivated LIGIV in the epithelial human cell line, HCT116. The resulting LIGIV-null cell line was viable, verifying that the gene and C-NHEJ are not essential. However, functional inactivation of RAD54B, a key homologous recombination factor, in the LIGIV-null background yielded no viable clones, suggesting that the combined absence of RAD54B/homologous recombination and C-NHEJ is synthetically lethal. Finally, we demonstrate that LIGIV is differentially required for certain chromosome fusion events induced by telomere dysfunction-used for those owing to the overexpression of a dominant negative version of telomere recognition factor 2, but not used for those owing to absence of Ku70:Ku86. |
| Databáze: | OpenAIRE |
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