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Molecules 2016, 21(6), 766; doi:10.3390/molecules21060766

Chemical Incorporation of Chain-Terminating Nucleoside Analogs as 3′-Blocking DNA Damage and Their Removal by Human ERCC1-XPF Endonuclease

1
Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
2
Department of Chemistry, Tokyo Metropolitan University, 1-1 Minami-Ohsawa, Hachi-Ohji, Tokyo 192-0397, Japan
*
Author to whom correspondence should be addressed.
Received: 13 May 2016 / Accepted: 3 June 2016 / Published: 11 June 2016
(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)
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Abstract

Nucleoside/nucleotide analogs that lack the 3′-hydroxy group are widely utilized for HIV therapy. These chain-terminating nucleoside analogs (CTNAs) block DNA synthesis after their incorporation into growing DNA, leading to the antiviral effects. However, they are also considered to be DNA damaging agents, and tyrosyl-DNA phosphodiesterase 1, a DNA repair enzyme, is reportedly able to remove such CTNA-modifications of DNA. Here, we have synthesized phosphoramidite building blocks of representative CTNAs, such as acyclovir, abacavir, carbovir, and lamivudine, and oligonucleotides with the 3′-CTNAs were successfully synthesized on solid supports. Using the chemically synthesized oligonucleotides, we investigated the excision of the 3′-CTNAs in DNA by the human excision repair cross complementing protein 1-xeroderma pigmentosum group F (ERCC1-XPF) endonuclease, which is one of the main components of the nucleotide excision repair pathway. A biochemical analysis demonstrated that the ERCC1-XPF endonuclease cleaved 2–7 nt upstream from the 3′-blocking CTNAs, and that DNA synthesis by the Klenow fragment was resumed after the removal of the CTNAs, suggesting that ERCC1-XPF participates in the repair of the CTNA-induced DNA damage. View Full-Text
Keywords: DNA damage; DNA repair; antiviral agents; solid-phase synthesis; nucleotide excision repair DNA damage; DNA repair; antiviral agents; solid-phase synthesis; nucleotide excision repair
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Yamamoto, J.; Takahata, C.; Kuraoka, I.; Hirota, K.; Iwai, S. Chemical Incorporation of Chain-Terminating Nucleoside Analogs as 3′-Blocking DNA Damage and Their Removal by Human ERCC1-XPF Endonuclease. Molecules 2016, 21, 766.

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