{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:45:16Z","timestamp":1768697116932,"version":"3.49.0"},"reference-count":29,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2016,6,11]],"date-time":"2016-06-11T00:00:00Z","timestamp":1465603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Culture, Sports, Science, and Technology","award":["1110104002"],"award-info":[{"award-number":["1110104002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Nucleoside\/nucleotide analogs that lack the 3\u2032-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\u2032-CTNAs were successfully synthesized on solid supports. Using the chemically synthesized oligonucleotides, we investigated the excision of the 3\u2032-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\u20137 nt upstream from the 3\u2032-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.<\/jats:p>","DOI":"10.3390\/molecules21060766","type":"journal-article","created":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T10:29:22Z","timestamp":1465813762000},"page":"766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chemical Incorporation of Chain-Terminating Nucleoside Analogs as 3\u2032-Blocking DNA Damage and Their Removal by Human ERCC1-XPF Endonuclease"],"prefix":"10.3390","volume":"21","author":[{"given":"Junpei","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiaki","family":"Takahata","sequence":"additional","affiliation":[{"name":"Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isao","family":"Kuraoka","sequence":"additional","affiliation":[{"name":"Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouji","family":"Hirota","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Tokyo Metropolitan University, 1-1 Minami-Ohsawa, Hachi-Ohji,  Tokyo 192-0397, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigenori","family":"Iwai","sequence":"additional","affiliation":[{"name":"Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8253","DOI":"10.1021\/bi801179f","article-title":"DNA polymerases as therapeutic targets","volume":"47","author":"Berdis","year":"2008","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1126\/science.1699273","article-title":"Molecular targets for AIDS therapy","volume":"249","author":"Mitsuya","year":"1990","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/nrd1201","article-title":"Mitochondrial toxicity of nrti antiviral drugs: an integrated cellular perspective","volume":"2","author":"Lewis","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23616","DOI":"10.1074\/jbc.M101114200","article-title":"Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma","volume":"276","author":"Lim","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"40847","DOI":"10.1074\/jbc.M106743200","article-title":"Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase","volume":"276","author":"Johnson","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14711","DOI":"10.1021\/bi035596s","article-title":"Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase","volume":"42","author":"Lee","year":"2003","journal-title":"Biochemistry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/S0021-9258(18)48361-5","article-title":"Interactions of azidothymidine triphosphate with the cellular DNA polymerases \u03b1, \u03b4, and \u03b5 and with DNA primase","volume":"267","author":"Nickel","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1126\/science.286.5439.552","article-title":"Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes","volume":"286","author":"Pouliot","year":"1999","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"19790","DOI":"10.1073\/pnas.1009814107","article-title":"Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria","volume":"107","author":"Das","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7793","DOI":"10.1093\/nar\/gkt483","article-title":"TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs","volume":"41","author":"Huang","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1400203","DOI":"10.1126\/sciadv.1400203","article-title":"Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia","volume":"1","author":"Tada","year":"2015","journal-title":"Sci. Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1128\/AAC.41.5.1099","article-title":"Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89","volume":"41","author":"Faletto","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_13","unstructured":"Vince, R., and Hua, M. (2006). Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, Inc.. Chapter 14, Unit 14.4."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8846","DOI":"10.1021\/ja050732x","article-title":"Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca2+-mobilizing second messenger. Structure-activity relationship of the N1-ribose moiety","volume":"127","author":"Kudoh","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1056\/NEJM198107093050202","article-title":"Acyclovir prophylaxis of herpes-simplex-virus infections","volume":"305","author":"Saral","year":"1981","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5520","DOI":"10.1021\/jm9007856","article-title":"The application of phosphoramidate protide technology to acyclovir confers anti-HIV inhibition","volume":"52","author":"Derudas","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23832","DOI":"10.1074\/jbc.M101156200","article-title":"Insights into the molecular mechanism of mitochondrial toxicity by AIDS drugs","volume":"276","author":"Feng","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1126\/science.8091230","article-title":"Specific cleavage of model recombination and repair intermediates by the yeast Rad1-Rad10 DNA endonuclease","volume":"265","author":"Bardwell","year":"1994","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/S0092-8674(00)80155-5","article-title":"Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease","volume":"86","author":"Sijbers","year":"1996","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7835","DOI":"10.1074\/jbc.273.14.7835","article-title":"DNA structural elements required for ERCC1-XPF endonuclease activity","volume":"273","author":"Appledoorn","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1093\/emboj\/21.11.2833","article-title":"Endogenous DNA abasic sites cause cell death in the absence of Apn1, Apn2 and Rad1\/Rad10 in Saccharomyces cerevisiae","volume":"21","author":"Guillet","year":"2002","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1021\/tx200221j","article-title":"Removal of reactive oxygen species-induced 3\u2032-blocked ends by XPF-ERCC1","volume":"24","author":"Fisher","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1093\/nar\/gkq1304","article-title":"Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells","volume":"39","author":"Zhang","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/carcin\/bgv078","article-title":"Repair synthesis step involving ERCC1-XPF participates in DNA repair of the Top1-DNA damage complex","volume":"36","author":"Takahata","year":"2015","journal-title":"Carcinogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/S0022-2836(03)00712-5","article-title":"Properties of and substrate determinants for the exonuclease activity of human apurinic endonuclease Ape1","volume":"330","author":"Wilson","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24176","DOI":"10.1074\/jbc.274.34.24176","article-title":"Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3\u2032-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage","volume":"274","author":"Jilani","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3797","DOI":"10.1093\/nar\/gkm158","article-title":"Aprataxin, causative gene product for EAOH\/AOA1, repairs DNA single-strand breaks with damaged 3\u2032-phosphate and 3\u2032-phosphoglycolate ends","volume":"35","author":"Takahashi","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1126\/science.1411547","article-title":"Removal of nonhomologous DNA ends in double-strand break recombination: the role of the yeast ultraviolet repair gene RAD1","volume":"258","author":"Haber","year":"1992","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.1128\/MCB.00293-08","article-title":"ERCC1-XPF endonuclease facilitates DNA double-strand break repair","volume":"28","author":"Ahmad","year":"2008","journal-title":"Mol. Cell. Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/6\/766\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:25:20Z","timestamp":1760210720000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/6\/766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,11]]},"references-count":29,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,6]]}},"alternative-id":["molecules21060766"],"URL":"https:\/\/doi.org\/10.3390\/molecules21060766","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,11]]}}}