Novel Enzymatic Function of DNA Polymerase ν in Translesion DNA Synthesis Past Major Groove DNA−Peptide and DNA−DNA Cross-Links
| Autor: | R. Stephen Lloyd, Carmelo J. Rizzo, Alexander Kolbanovskiy, Richard D. Wood, Kinrin Yamanaka, Irina G. Minko, Ivan D. Kozekov, Kei Ichi Takata |
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| Rok vydání: | 2010 |
| Předmět: |
DNA Replication
DNA Repair DNA polymerase Stereochemistry DNA polymerase II DNA-Directed DNA Polymerase Toxicology DNA polymerase delta Article Substrate Specificity DNA Adducts 03 medical and health sciences Humans 030304 developmental biology 0303 health sciences DNA clamp biology 030302 biochemistry & molecular biology DNA polymerase V DNA replication DNA General Medicine Processivity Molecular biology biology.protein Peptides DNA polymerase mu DNA Damage |
| Zdroj: | Chemical Research in Toxicology |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/tx900449u |
| Popis: | DNA polymerase nu (POLN or pol nu) is a newly discovered A family polymerase that generates a high error rate when incorporating nucleotides opposite dG; its translesion DNA synthesis (TLS) capability has only been demonstrated for high fidelity replication bypass of thymine glycol lesions. In the current investigation, we describe a novel TLS substrate specificity of pol nu, demonstrating that it is able to bypass exceptionally large DNA lesions whose linkages are through the DNA major groove. Specifically, pol nu catalyzed efficient and high fidelity TLS past peptides linked to N(6)-dA via a reduced Schiff base linkage with a gamma-hydroxypropano-dA. Additionally, pol nu could bypass DNA interstrand cross-links with linkage between N(6)-dAs in complementary DNA strands. However, the chemically identical DNA--peptide and DNA interstrand cross-links completely blocked pol nu when they were located in the minor groove via a N(2)-dG linkage. Furthermore, we showed that pol nu incorporated a nucleotide opposite the 1,N(6)-etheno-dA (epsilondA) in an error-free manner and (+)-trans-anti-benzo[a]pyrene-7,8-dihydrodiol 9,10-epoxide-dA [(+)-BPDE-dA] in an error-prone manner, albeit with a greatly reduced capability. Collectively, these data suggest that although pol nu bypass capacity cannot be generalized to all major groove DNA adducts, this polymerase could be involved in TLS when genomic replication is blocked by extremely large major groove DNA lesions. In view of the recent observation that pol nu may have a role in cellular tolerance to DNA cross-linking agents, our findings provide biochemical evidence for the potential functioning of this polymerase in the bypass of some DNA-protein and DNA-DNA cross-links. |
| Databáze: | OpenAIRE |
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