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

Yamamoto, Junpei; Takahata, Chiaki; Kuraoka, Isao; Hirota, Kouji; Iwai, Shigenori

doi:10.3390/molecules21060766

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

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Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan

Department of Chemistry, Tokyo Metropolitan University, 1-1 Minami-Ohsawa, Hachi-Ohji, Tokyo 192-0397, Japan

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

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

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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. https://doi.org/10.3390/molecules21060766

AMA Style

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(6):766. https://doi.org/10.3390/molecules21060766

Chicago/Turabian Style

Yamamoto, Junpei, Chiaki Takahata, Isao Kuraoka, Kouji Hirota, and Shigenori Iwai. 2016. "Chemical Incorporation of Chain-Terminating Nucleoside Analogs as 3′-Blocking DNA Damage and Their Removal by Human ERCC1-XPF Endonuclease" Molecules 21, no. 6: 766. https://doi.org/10.3390/molecules21060766

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

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