Excessive reactive oxygen species induce transcription-dependent replication stress

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...

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Veröffentlicht in:Nature communications Jg. 14; H. 1; S. 1791 - 15
Hauptverfasser: Andrs, Martin, Stoy, Henriette, Boleslavska, Barbora, Chappidi, Nagaraja, Kanagaraj, Radhakrishnan, Nascakova, Zuzana, Menon, Shruti, Rao, Satyajeet, Oravetzova, Anna, Dobrovolna, Jana, Surendranath, Kalpana, Lopes, Massimo, Janscak, Pavel
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 30.03.2023
Nature Publishing Group
Nature Portfolio
Schlagworte:
13/1
13/106
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13/51
14/28
14/35
14/63
38/22
38/77
631/337/1427
631/337/151/2356
Aphidicolin
Cancer
Chromosome rearrangements
Deoxyribonucleic acid
Depletion
DNA
DNA damage
DNA polymerase
DNA Replication
DNA-Binding Proteins - metabolism
DNA-directed DNA polymerase
Humanities and Social Sciences
Humans
Hybrids
Hydroxyurea
Hydroxyurea - pharmacology
multidisciplinary
Oxidative stress
Oxygen
R-loops
Reactive Oxygen Species
Reductases
Replication
S Phase - genetics
Science
Science (multidisciplinary)
Stalling
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ISSN:2041-1723, 2041-1723
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Zusammenfassung: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. Excessive oxidative stress is widely perceived as a key factor in cancer progression. Here, the authors reveal that oxidative stress induces transcription-dependent replication fork stalling that appears to be a major source of chromosomal rearrangements found in human cancers.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-37341-y