Excessive reactive oxygen species induce transcription-dependent replication stress

Martin Andrs, Henriette Stoy, Barbora Boleslavska, Nagaraja Chappidi, Radhakrishnan Kanagaraj, Zuzana Nascakova, Shruti Menon, Satyajeet Rao, Anna Oravetzova, Jana Dobrovolna, Kalpana Surendranath, Massimo Lopes and Pavel Janscak ()
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Martin Andrs: Institute of Molecular Genetics of the Czech Academy of Sciences
Henriette Stoy: University of Zurich
Barbora Boleslavska: Institute of Molecular Genetics of the Czech Academy of Sciences
Nagaraja Chappidi: University of Zurich
Radhakrishnan Kanagaraj: University of Westminster
Zuzana Nascakova: Institute of Molecular Genetics of the Czech Academy of Sciences
Shruti Menon: University of Zurich
Satyajeet Rao: University of Zurich
Anna Oravetzova: Institute of Molecular Genetics of the Czech Academy of Sciences
Jana Dobrovolna: Institute of Molecular Genetics of the Czech Academy of Sciences
Kalpana Surendranath: University of Westminster
Massimo Lopes: University of Zurich
Pavel Janscak: Institute of Molecular Genetics of the Czech Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37341-y

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