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

Sehyun Oh, Yongbao Wang, Jacob Zimbric, Eric A Hendrickson

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Classic non-homologous end joining (C-NHEJ) is the predominant DNA double-strand break repair pathway in humans. Although seven genes Ku70, Ku86, DNA-PKcs, 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.

Original languageEnglish (US)
Pages (from-to)1734-1749
Number of pages16
JournalNucleic acids research
Volume41
Issue number3
DOIs
StatePublished - Feb 2013

Bibliographical note

Funding Information:
Conflict of interest statement. E.A.H. declares that he is a member of the scientific advisory board of Horizon Discovery, Ltd., a company that specializes in rAAV-mediated gene targeting technology and that his laboratory is funded, in part, through a research contract from the same company.

Funding Information:
Funding for open access charge: National Institutes of Health [GM088351]; National Cancer Institute [CA154461]; Horizon Discovery, Ltd.

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