Excessive reactive oxygen species induce transcription-dependent replication stress

0571218 - ÚMG 2024 RIV US eng J - Journal Article
Andrš, Martin - Stoy, H. - Boleslavská, Barbora - Chappidi, N. - Kanagaraj, R. - Naščáková, Zuzana - Menon, S. - Rao, S. - Oravetzová, Anna - Dobrovolná, Jana - Surendranath, K. - Lopes, M. - Janščák, Pavel
Excessive reactive oxygen species induce transcription-dependent replication stress.
Nature Communications. Roč. 14, č. 1 (2023), č. článku 1791. E-ISSN 2041-1723
R&D Projects: GA MŠMT(CZ) EF18_046/0016045; GA MŠMT(CZ) LM2018129; GA ČR GA22-08294S; GA ČR GX21-22593X
Institutional support: RVO:68378050
Keywords : DNA-REPLICATION * GENOMIC INSTABILITY * FORK REVERSAL * R-LOOPS * DAMAGE * ARCHITECTURE * CONFLICTS * YEAST
OECD category: Biology (theoretical, mathematical, thermal, cryobiology, biological rhythm), Evolutionary biology
Impact factor: 16.6, year: 2022
Method of publishing: Open access
https://www.nature.com/articles/s41467-023-37341-y

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.
Permanent Link: https://hdl.handle.net/11104/0342497