Title | Excessive reactive oxygen species induce transcription-dependent replication stress. |
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Type | Journal article |
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Authors | Andrs, Martin, Stoy, H., Boleslavska, Barbora, Chappidi, Nagaraja, Kanagaraj, R., Nascakova, Zuzana, Menon, Shruti, Rao, Satyajeet, Oravetzova, Anna, Dobrovolna, J., Surendranath, Kalpana, Lopes, M. and Janscak, P. |
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Abstract | Elevated levels of reactive oxygen species (ROS) reduce replication fork velocity by causing dissociation of the TIMELESS-TIPIN complex from the replisome. Here, we show that ROS generated by exposure of human cells to the ribonucleotide reductase inhibitor hydroxyurea (HU) promote replication fork reversal in a manner dependent on active transcription and formation of co-transcriptional RNA:DNA hybrids (R-loops). The frequency of R-loop-dependent fork stalling events is also increased after TIMELESS depletion or a partial inhibition of replicative DNA polymerases by aphidicolin, suggesting that this phenomenon is due to a global replication slowdown. In contrast, replication arrest caused by HU-induced depletion of deoxynucleotides does not induce fork reversal but, if allowed to persist, leads to extensive R-loop-independent DNA breakage during S-phase. Our work reveals a link between oxidative stress and transcription-replication interference that causes genomic alterations recurrently found in human cancer. [Abstract copyright: © 2023. The Author(s).] |
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Keywords | S Phase - genetics |
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| Reactive Oxygen Species |
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| Hydroxyurea - pharmacology |
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| DNA Replication |
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| Humans |
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| DNA |
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| DNA-Binding Proteins - metabolism |
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Article number | 1791 |
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Journal | Nature Communications |
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Journal citation | 14 (1) |
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ISSN | 2041-1723 |
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Year | 2023 |
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Publisher | Nature Publishing Group |
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Publisher's version | License CC BY 4.0 File Access Level Open (open metadata and files) |
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Digital Object Identifier (DOI) | https://doi.org/10.1038/s41467-023-37341-y |
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PubMed ID | 36997515 |
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Publication dates |
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Published online | 30 Mar 2023 |
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