| Title | Excessive reactive oxygen species induce transcription-dependent replication stress. |
|---|
| Type | Journal article |
|---|
| 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. |
|---|
| Janscak, P. |
|---|
| 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).] |
|---|
| Keywords | S Phase - genetics |
|---|
| Reactive Oxygen Species |
|---|
| Hydroxyurea - pharmacology |
|---|
| DNA Replication |
|---|
| Humans |
|---|
| DNA |
|---|
| DNA-Binding Proteins - metabolism |
|---|
| Article number | 1791 |
|---|
| Journal | Nature Communications |
|---|
| Journal citation | 14 (1) |
|---|
| ISSN | 2041-1723 |
|---|
| Year | 2023 |
|---|
| Publisher | Nature 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 ID | 36997515 |
|---|
| Publication dates |
|---|
| Published online | 30 Mar 2023 |
|---|