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Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction

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 anc...

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Autores principales: Oh, Sehyun, Wang, Yongbao, Zimbric, Jacob, Hendrickson, Eric A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561972/
https://www.ncbi.nlm.nih.gov/pubmed/23275564
http://dx.doi.org/10.1093/nar/gks1326
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author Oh, Sehyun
Wang, Yongbao
Zimbric, Jacob
Hendrickson, Eric A.
author_facet Oh, Sehyun
Wang, Yongbao
Zimbric, Jacob
Hendrickson, Eric A.
author_sort Oh, Sehyun
collection PubMed
description 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.
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spelling pubmed-35619722013-02-01 Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction Oh, Sehyun Wang, Yongbao Zimbric, Jacob Hendrickson, Eric A. Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2013-02 2012-12-26 /pmc/articles/PMC3561972/ /pubmed/23275564 http://dx.doi.org/10.1093/nar/gks1326 Text en © The Author(s) 2012. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
spellingShingle Genome Integrity, Repair and Replication
Oh, Sehyun
Wang, Yongbao
Zimbric, Jacob
Hendrickson, Eric A.
Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction
title Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction
title_full Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction
title_fullStr Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction
title_full_unstemmed Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction
title_short Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction
title_sort human ligiv is synthetically lethal with the loss of rad54b-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561972/
https://www.ncbi.nlm.nih.gov/pubmed/23275564
http://dx.doi.org/10.1093/nar/gks1326
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