Excessive reactive oxygen species induce transcription-dependent replication stress.

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. 2023. Excessive reactive oxygen species induce transcription-dependent replication stress. Nature Communications . 14 (1) 1791. https://doi.org/10.1038/s41467-023-37341-y

TitleExcessive reactive oxygen species induce transcription-dependent replication stress.
TypeJournal article
AuthorsAndrs, Martin
Stoy, H.
Boleslavska, Barbora
Chappidi, Nagaraja
Kanagaraj, R.
Nascakova, Zuzana
Menon, Shruti
Rao, Satyajeet
Oravetzova, Anna
Dobrovolna, J.
Surendranath, Kalpana
Lopes, M.
Janscak, P.
AbstractElevated 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).]
KeywordsS Phase - genetics
Reactive Oxygen Species
Hydroxyurea - pharmacology
DNA Replication
Humans
DNA
DNA-Binding Proteins - metabolism
Article number1791
JournalNature Communications
Journal citation14 (1)
ISSN2041-1723
Year2023
PublisherNature Publishing Group
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1038/s41467-023-37341-y
PubMed ID36997515
Publication dates
Published online30 Mar 2023

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