Excision of Carbohydrate-Modified dNMP Analogues from DNA 3' end by Human Apurinic/Apyrimidinic Endonuclease 1 (APE1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1)

• Published in: Molecular biology (New York) 2018-11, Vol.52 (6), p.922-928
• Main Authors: Dyrkheeva, N. S., Lebedeva, N. A., Sherstyuk, Yu. V., Abramova, T. V., Silnikov, V. N., Lavrik, O. I.
• Format: Article
• Language: English
• Subjects: Antiviral agents; Biochemistry; Biomedical and Life Sciences; Cytosine; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA polymerase; DNA repair; DNA-directed DNA polymerase; Endonuclease; HIV; Human Genetics; Human immunodeficiency virus; Insertion; Life Sciences; Nucleosides; Nucleotides; Phosphodiesterase; Primers; Proofreading; Ribonucleic acid; Ribose; RNA; RNA-directed DNA polymerase; Structural-Functional Analysis of Biopolymers and Their Complexes
• ISSN: 0026-8933; 1608-3245
• DOI: 10.1134/S0026893318060067

We have studied the excision efficiency of human apurinic/apyrimidinic endonuclease 1 (APE1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) on matched or mismatched bases located at the 3' end of DNA primers. We have used model DNA duplexes, which mimic DNA structures that occur during either replication (DNA with a 3' recessed end) or repair (DNA with a single-strand break). Both APE1 and TDP1 are more efficient in removing ribose-modified dNMP residues from mismatched pairs rather than canonical pairs. Thus, both of these enzymes may act as proofreading factors during the repair synthesis catalyzed by DNA polymerases including DNA polymerase β (Polβ). The design of new DNA polymerase inhibitors, which act as DNA or RNA chain terminators, is one of the main strategies in the development of antiviral agents. The excision efficacy of APE1 and TDP1 has also been studied for 3'-modified DNA duplexes that contain ddNMP or phosphorylated morpholino nucleosides (MorB) commonly used as terminators in the DNA synthesis. We have also investigated the insertion of ddNTP and morpholino nucleotides catalyzed by Polβ and human immunodeficiency virus reverse transcriptase. This experiment has pointed to MorCyt, cytosine-containing morpholino nucleoside, as a potential antiviral agent.