Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity
Abstract: DNA single‐strand breaks (SSBs) disrupt DNA replication and induce chromosome breakage. However, whether SSBs induce chromosome breakage when present behind replication forks or ahead of replication forks is unclear. To address this question, we exploited an exquisite sensitivity of SSB repair‐defective human cells lacking PARP activity or XRCC1 to the thymidine analogue 5‐chloro‐2′‐deoxyuridine (CldU). We show that incubation with CldU in these cells results in chromosome breakage, sister chromatid exchange, and cytotoxicity by a mechanism that depends on the S phase activity of uracil DNA glycosylase (UNG). Importantly, we show that CldU incorporation in one cell cycle is cytotoxic only during the following cell cycle, when it is present in template DNA. In agreement with this, while UNG induces SSBs both in nascent strands behind replication forks and in template strands ahead of replication forks, only the latter trigger fork collapse and chromosome breakage. Finally, we show that BRCA‐defective cells are hypersensitive to CldU, either alone and/or in combination with PARP inhibitor, suggesting that CldU may have clinical utility.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity ; day:26 ; month:07 ; year:2023 ; extent:19
The EMBO journal / European Molecular Biology Organization ; (26.07.2023) (gesamt 19)
- Urheber
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Serrano‐Benitez, Almudena
Wells, Sophie E.
Drummond‐Clarke, Lylah
Russo, Lilian C.
Thomas, John Christopher
Leal, Giovanna A.
Farrow, Mark
Edgerton, James Michael
Balasubramanian, Shankar
Yang, Ming
Frezza, Christian
Gautam, Amit
Brazina, Jan
Burdova, Kamila
Hoch, Nicolas C.
Jackson, Stephen P.
Caldecott, Keith W.
- DOI
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10.15252/embj.2022113190
- URN
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urn:nbn:de:101:1-2023072615221393340600
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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14.08.2025, 10:53 MESZ
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Beteiligte
- Serrano‐Benitez, Almudena
- Wells, Sophie E.
- Drummond‐Clarke, Lylah
- Russo, Lilian C.
- Thomas, John Christopher
- Leal, Giovanna A.
- Farrow, Mark
- Edgerton, James Michael
- Balasubramanian, Shankar
- Yang, Ming
- Frezza, Christian
- Gautam, Amit
- Brazina, Jan
- Burdova, Kamila
- Hoch, Nicolas C.
- Jackson, Stephen P.
- Caldecott, Keith W.
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