Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair
Melike Çağlayan1, Samuel H Wilson1
1Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Abstract:
DNA lesions arise from many endogenous and environmental agents, and such lesions can promote deleterious events leading to genomic instability and cell death. Base excision repair (BER) is the main DNA repair pathway responsible for repairing single strand breaks, base lesions and abasic sites in mammalian cells. During BER, DNA substrates and repair intermediates are channeled from one step to the next in a sequential fashion so that release of toxic repair intermediates is minimized. This includes handoff of the product of gap-filling DNA synthesis to the DNA ligation step. The conformational differences in DNA polymerase β (pol β) associated with incorrect or oxidized nucleotide (8-oxodGMP) insertion could impact channeling of the repair intermediate to the final step of BER, i.e., DNA ligation by DNA ligase I or the DNA Ligase III/XRCC1 complex. Thus, modified DNA ligase substrates produced by faulty pol β gap-filling could impair coordination between pol β and DNA ligase. Ligation failure is associated with 5'-AMP addition to the repair intermediate and accumulation of strand breaks that could be more toxic than the initial DNA lesions. Here, we provide an overview of the consequences of ligation failure in the last step of BER. We also discuss DNA-end processing mechanisms that could play roles in reversal of impaired BER.
Insights
Base excision repair (BER) prevents genomic instability. Ligation failure during BER, caused by DNA polymerase errors, leads to toxic DNA strand breaks, impairing cellular repair mechanisms.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- DNA lesions from endogenous and environmental factors can cause genomic instability.
- Base excision repair (BER) is crucial for repairing DNA base lesions and strand breaks in mammalian cells.
- Efficient channeling of repair intermediates is vital during BER to prevent accumulation of toxic species.
Purpose of the Study:
- To explore the consequences of ligation failure in the final step of BER.
- To investigate how DNA polymerase errors impact the BER pathway.
- To discuss DNA-end processing mechanisms that may reverse impaired BER.
Main Methods:
- Review of existing literature on BER pathway and DNA repair mechanisms.
- Analysis of the role of DNA polymerase β (pol β) in nucleotide insertion and its impact on ligation.
- Examination of the consequences of ligation failure, including 5'-AMP addition and strand break accumulation.
Main Results:
- Faulty nucleotide insertion by pol β can create modified DNA ligase substrates.
- Impaired coordination between pol β and DNA ligase can lead to ligation failure.
- Ligation failure results in 5'-AMP addition and accumulation of potentially toxic DNA strand breaks.
Conclusions:
- Ligation failure represents a critical bottleneck in BER, potentially exacerbating DNA damage.
- Understanding these failures is key to comprehending genomic instability.
- DNA-end processing mechanisms may offer pathways to mitigate the effects of impaired BER.
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