Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases
8-oxo-guanine (8OG) is a common base lesion, generated by reactive oxygen species, which has been associated with human diseases such as cancer, aging-related neurodegenerative disorders and atherosclerosis. 8OG is highly mutagenic, due to its dual-coding potential it can pair both with adenine or c...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/1/15 |
| _version_ | 1797493865965420544 |
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| author | Andrea M. Kaminski Thomas A. Kunkel Lars C. Pedersen Katarzyna Bebenek |
| author_facet | Andrea M. Kaminski Thomas A. Kunkel Lars C. Pedersen Katarzyna Bebenek |
| author_sort | Andrea M. Kaminski |
| collection | DOAJ |
| description | 8-oxo-guanine (8OG) is a common base lesion, generated by reactive oxygen species, which has been associated with human diseases such as cancer, aging-related neurodegenerative disorders and atherosclerosis. 8OG is highly mutagenic, due to its dual-coding potential it can pair both with adenine or cytidine. Therefore, it creates a challenge for DNA polymerases striving to correctly replicate and/or repair genomic or mitochondrial DNA. Numerous structural studies provide insights into the mechanistic basis of the specificity of 8OG bypass by DNA polymerases from different families. Here, we focus on how repair polymerases from Family X (Pols β, λ and µ) engage DNA substrates containing the oxidized guanine. We review structures of binary and ternary complexes for the three polymerases, which represent distinct steps in their catalytic cycles—the binding of the DNA substrate and the incoming nucleotide, followed by its insertion and extension. At each of these steps, the polymerase may favor or exclude the correct C or incorrect A, affecting the final outcome, which varies depending on the enzyme. |
| first_indexed | 2024-03-10T01:26:06Z |
| format | Article |
| id | doaj.art-a6a11c05e30648aabe876533a08f9392 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T01:26:06Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-a6a11c05e30648aabe876533a08f93922023-11-23T13:51:04ZengMDPI AGGenes2073-44252021-12-011311510.3390/genes13010015Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA PolymerasesAndrea M. Kaminski0Thomas A. Kunkel1Lars C. Pedersen2Katarzyna Bebenek3Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Bldg. 101, Durham, NC 27709, USAGenome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Bldg. 101, Durham, NC 27709, USAGenome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Bldg. 101, Durham, NC 27709, USAGenome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Bldg. 101, Durham, NC 27709, USA8-oxo-guanine (8OG) is a common base lesion, generated by reactive oxygen species, which has been associated with human diseases such as cancer, aging-related neurodegenerative disorders and atherosclerosis. 8OG is highly mutagenic, due to its dual-coding potential it can pair both with adenine or cytidine. Therefore, it creates a challenge for DNA polymerases striving to correctly replicate and/or repair genomic or mitochondrial DNA. Numerous structural studies provide insights into the mechanistic basis of the specificity of 8OG bypass by DNA polymerases from different families. Here, we focus on how repair polymerases from Family X (Pols β, λ and µ) engage DNA substrates containing the oxidized guanine. We review structures of binary and ternary complexes for the three polymerases, which represent distinct steps in their catalytic cycles—the binding of the DNA substrate and the incoming nucleotide, followed by its insertion and extension. At each of these steps, the polymerase may favor or exclude the correct C or incorrect A, affecting the final outcome, which varies depending on the enzyme.https://www.mdpi.com/2073-4425/13/1/15Family X polymerases8-oxo-guanine (8OG)oxidized base damageDNA repairbase excision repair (BER)nonhomologous end-joining (NHEJ) |
| spellingShingle | Andrea M. Kaminski Thomas A. Kunkel Lars C. Pedersen Katarzyna Bebenek Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases Genes Family X polymerases 8-oxo-guanine (8OG) oxidized base damage DNA repair base excision repair (BER) nonhomologous end-joining (NHEJ) |
| title | Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases |
| title_full | Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases |
| title_fullStr | Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases |
| title_full_unstemmed | Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases |
| title_short | Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases |
| title_sort | structural insights into the specificity of 8 oxo 7 8 dihydro 2 deoxyguanosine bypass by family x dna polymerases |
| topic | Family X polymerases 8-oxo-guanine (8OG) oxidized base damage DNA repair base excision repair (BER) nonhomologous end-joining (NHEJ) |
| url | https://www.mdpi.com/2073-4425/13/1/15 |
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