DNA ligase III and DNA ligase IV carry out genetically distinct forms of end joining in human somatic cells
Open accessAbstract
Ku-dependent C-NHEJ (classic non-homologous end joining) is the primary DNA EJing (end joining) repair pathway in mammals. Recently, an additional EJing repair pathway (A-NHEJ; alternative-NHEJ) has been described. Currently, the mechanism of A-NHEJ is obscure although a dependency on LIGIII (DNA ligase III) is often implicated. To test the requirement for LIGIII in A-NHEJ we constructed a LIGIII conditionally-null human cell line using gene targeting. Nuclear EJing activity appeared unaffected by a deficiency in LIGIII as, surprisingly, so were random gene targeting integration events. In contrast, LIGIII was required for mitochondrial function and this defined the gene's essential activity. Human Ku:LIGIII and Ku:LIGIV (DNA ligase IV) double knockout cell lines, however, demonstrated that LIGIII is required for the enhanced A-NHEJ activity that is observed in Ku-deficient cells. Most unexpectedly, however, the majority of EJing events remained LIGIV-dependent. In conclusion, although human LIGIII has an essential function in mitochondrial maintenance, it is dispensable for most types of nuclear DSB repair, except for the A-NHEJ events that are normally suppressed by Ku. Moreover, we describe that a robust Ku-independent, LIGIV-dependent repair pathway exists in human somatic cells.
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Telomere fusions formed during telomere crisis in cultured cells are mediated by alt-NHEJ and show insertion of new sequences at the fusion point.
“Telomere fusions formed during telomere crisis in cultured cells are mediated by alt-NHEJ and exhibit insertion of new sequences at the fusion point75,76.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [76]
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“HCT116 LIG3flox/ cells containing a conditional LIG3 allele and a deletion allele (Oh et al., 2014) were further engineered to express human LIG1 with a mitochondrial leader sequence (MtLIG1).”
BackgroundInfluentialSelf-citationEscape from Telomere-Driven Crisis Is DNA Ligase III Dependent
Jones, R. E., Oh, S., Grimstead, J. W., Zimbric, J., Roger, L., Heppel, N. H., Ashelford, K. E., Liddiard, K., Hendrickson, E. A., & Baird, D. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.007 · Cited by 74 · see citing works
Self-citation
- Authors
- Oh, S., Harvey, A., Zimbric, J., Wang, Y., Nguyen, T., Jackson, P. J., & Hendrickson, E. A.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Hendrickson, Eric A.
- Venue
- DNA Repair
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 21
- Pages
- 97-110
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- PMC
- PMC4125535
- OpenAlex
- W1964495746
- Cited by
- 58
- References
- 71
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 8 · 2016: 5 · 2015: 16 · 2014: 4 · 2012: 1
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA154461, CA154461)
- National Institute of General Medical Sciences (R01GM088351, GM088351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- DNA ligase III, DNA ligase IV, alternative non-homologous end joining, Ku protein, DNA double-strand break repair, mitochondrial function, human somatic cells
- MeSH terms
- Ku Autoantigen, DNA Ligase ATP, Poly-ADP-Ribose Binding Proteins, Cell Line, DNA-Binding Proteins, Humans, DNA Ligases, Xenopus Proteins, Antigens, Nuclear, HCT116 Cells, DNA End-Joining Repair
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