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Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair

Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorpora...

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Autores principales: Bulgar, A D, Weeks, L D, Miao, Y, Yang, S, Xu, Y, Guo, C, Markowitz, S, Oleinick, N, Gerson, S L, Liu, L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270269/
https://www.ncbi.nlm.nih.gov/pubmed/22237209
http://dx.doi.org/10.1038/cddis.2011.135
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author Bulgar, A D
Weeks, L D
Miao, Y
Yang, S
Xu, Y
Guo, C
Markowitz, S
Oleinick, N
Gerson, S L
Liu, L
author_facet Bulgar, A D
Weeks, L D
Miao, Y
Yang, S
Xu, Y
Guo, C
Markowitz, S
Oleinick, N
Gerson, S L
Liu, L
author_sort Bulgar, A D
collection PubMed
description Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG(+/+)/UDG(−/−)). UDG(−/−) cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG(+/+) cells were >10 times more resistant to pemetrexed due to the rapid removal of uracil from DNA by UDG and subsequent repair of the resultant AP sites (abasic sites) via the base excision repair (BER). The resistance to pemetrexed in UDG(+/+) cells could be reversed by the addition of methoxyamine (MX), which binds to AP sites and interrupts BER pathway. Furthermore, MX-bound AP sites induced cell death was related to their cytotoxic effect of dual inactivation of UDG and topoisomerase IIα, two genes that are highly expressed in lung cancer cells in comparison with normal cells. Thus, targeting BER-based therapy exhibits more selective cytotoxicity on cancer cells through a synthetic lethal mechanism.
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spelling pubmed-32702692012-02-02 Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair Bulgar, A D Weeks, L D Miao, Y Yang, S Xu, Y Guo, C Markowitz, S Oleinick, N Gerson, S L Liu, L Cell Death Dis Original Article Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG(+/+)/UDG(−/−)). UDG(−/−) cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG(+/+) cells were >10 times more resistant to pemetrexed due to the rapid removal of uracil from DNA by UDG and subsequent repair of the resultant AP sites (abasic sites) via the base excision repair (BER). The resistance to pemetrexed in UDG(+/+) cells could be reversed by the addition of methoxyamine (MX), which binds to AP sites and interrupts BER pathway. Furthermore, MX-bound AP sites induced cell death was related to their cytotoxic effect of dual inactivation of UDG and topoisomerase IIα, two genes that are highly expressed in lung cancer cells in comparison with normal cells. Thus, targeting BER-based therapy exhibits more selective cytotoxicity on cancer cells through a synthetic lethal mechanism. Nature Publishing Group 2012-01 2012-01-12 /pmc/articles/PMC3270269/ /pubmed/22237209 http://dx.doi.org/10.1038/cddis.2011.135 Text en Copyright © 2012 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Bulgar, A D
Weeks, L D
Miao, Y
Yang, S
Xu, Y
Guo, C
Markowitz, S
Oleinick, N
Gerson, S L
Liu, L
Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair
title Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair
title_full Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair
title_fullStr Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair
title_full_unstemmed Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair
title_short Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair
title_sort removal of uracil by uracil dna glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270269/
https://www.ncbi.nlm.nih.gov/pubmed/22237209
http://dx.doi.org/10.1038/cddis.2011.135
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