Alternative Okazaki Fragment Ligation Pathway by DNA Ligase III
Abstract
:1. Introduction
2. DNA Ligase Responsible for the Ligation of Okazaki Fragments
3. Has Lig3 A Function in DNA Replication Outside Mitochondria?
4. Why is Mitochondrial Lig3 Essential?
5. Alternative Okazaki-Fragment Ligation Pathway by Lig3
6. Lig3 as a Universal DNA Ligase
7. Conclusions
Concept | Lig1 | Lig3 | Lig4 |
---|---|---|---|
classical concept | DNA replication | BER (short patch) | NHEJ |
BER (long patch) | mitochondria | V(D)J recombination | |
HR | class switch recombination | ||
NER | |||
new concept | DNA replication | DNA replication | NHEJ |
BER (long patch) | BER (short patch) | V(D)J recombination | |
HR | HR | class switch recombination | |
NER | NER | ||
B-NHEJ | B-NHEJ | ||
(V(D)J recombination?) | (V(D)J recombination?) | ||
(class switch recombination?) | (class switch recombination?) | ||
mitochondria |
8. Future Perspectives
- As Lig1 knockout DT40 cells proliferate normally, it must be assumed that Lig3 is recruited to DNA replication sites as effectively as Lig1. How is this achieved and how do cells chose between the two DNA ligases?
- It has been reported that Lig1 and Lig3 have a significant contribution to translocation formation in rodent cell systems [59,60,61]. In human cells, classical NHEJ, and thus Lig4, has a bulk contribution to chromosome translocation formation initiated by DSB induced by designer nucleases [62]. However, chromosome translocations generated in human cells exposed during the G2-phase to IR, which induces DSB randomly distributed throughout the genome, largely rely on Lig1 and Lig3 as is the case in rodent cells [63]. This raises the question of the evolutionary significance of Lig3 in chromosomal translocation formation, and thus in the development of cancer.
- Why mitochondria are served in vertebrates preferentially by Lig3 over Lig1, and why did Lig1 lose this duty during evolution?
- As Xrcc1 is not necessary for the mitochondrial functions of Lig3, it can be inferred that Lig3 can also function without this cofactor. This raises the question as to whether certain aspects of the nuclear functions of Lig3 are also Xrcc1-independent.
- Lig3 may have important partners in addition to Xrcc1. Indeed, Lig3 may change partners depending upon the process it is involved, and possibly also the cellular physiology. What are these partners and what is the functional significance of the corresponding interactions?
- Although Lig2 is considered at present a biochemical artefact, the possibility should be left open that it is more than a random degradation product of Lig3: it may well be the fifth variant of Lig3 endowed with specific but as of yet uncharacterized functions.
- Is Lig1 knockout in the mouse lethal if mediated by Cre/lox P in adult stage, where Lig3 should be able to fully compensate?
Acknowledgments
Conflicts of Interest
Abbreviations
BER | Base excision repair |
BRCA1 | breast cancer susceptibility gene 1 |
BRCT | BRCA1 C terminus |
B-NHEJ | back up-NHEJ |
C-NHEJ | classical non-homologous end-joining |
Lig1 | DNA ligase 1 |
Lig2 | DNA ligase 2 |
Lig3 | DNA ligase 3 |
Lig4 | DNA ligase 4 |
IR | ionizing radiation |
DSB | double strand break |
HRR | homologous recombination repair |
MEF | mouse embryonic fibroblasts |
MTS | mitochondria target sequence |
NER | nucleotide excision repair |
SSBR | single strand break repair |
PCNA | proliferating cell nuclear antigen |
XRCC1 | X-ray repair cross-complementing protein 1 |
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Arakawa, H.; Iliakis, G. Alternative Okazaki Fragment Ligation Pathway by DNA Ligase III. Genes 2015, 6, 385-398. https://doi.org/10.3390/genes6020385
Arakawa H, Iliakis G. Alternative Okazaki Fragment Ligation Pathway by DNA Ligase III. Genes. 2015; 6(2):385-398. https://doi.org/10.3390/genes6020385
Chicago/Turabian StyleArakawa, Hiroshi, and George Iliakis. 2015. "Alternative Okazaki Fragment Ligation Pathway by DNA Ligase III" Genes 6, no. 2: 385-398. https://doi.org/10.3390/genes6020385