PLoS genetics, 2022-12, Vol.18 (12), p.e1010309-e1010309
2022
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Details
- Autor(en) / Beteiligte
- Titel
- RAD18 opposes transcription-associated genome instability through FANCD2 recruitment
- Ist Teil von
- PLoS genetics, 2022-12, Vol.18 (12), p.e1010309-e1010309
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- DNA replication is a vulnerable time for genome stability maintenance. Intrinsic stressors, as well as oncogenic stress, can challenge replication by fostering conflicts with transcription and stabilizing DNA:RNA hybrids. RAD18 is an E3 ubiquitin ligase for PCNA that is involved in coordinating DNA damage tolerance pathways to preserve genome stability during replication. In this study, we show that RAD18 deficient cells have higher levels of transcription-replication conflicts and accumulate DNA:RNA hybrids that induce DNA double strand breaks and replication stress. We find that these effects are driven in part by failure to recruit the Fanconi Anemia protein FANCD2 at difficult to replicate and R-loop prone genomic sites. FANCD2 activation caused by splicing inhibition or aphidicolin treatment is critically dependent on RAD18 activity. Thus, we highlight a RAD18-dependent pathway promoting FANCD2-mediated suppression of R-loops and transcription-replication conflicts.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7404, 1553-7390eISSN: 1553-7404DOI: 10.1371/journal.pgen.1010309Titel-ID: cdi_plos_journals_2766097960
- Format
- –
- Schlagworte
- Analysis, Anemia, Aphidicolin, Biology and life sciences, Cancer, Control, CRISPR, Deoxyribonucleic acid, DNA, DNA - genetics, DNA biosynthesis, DNA damage, DNA Damage - genetics, DNA repair, DNA Repair - genetics, DNA replication, DNA Replication - genetics, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Fanconi Anemia - genetics, Fanconi Anemia - metabolism, Fanconi Anemia Complementation Group D2 Protein - metabolism, Fanconi syndrome, Fanconi's anemia, Genetic research, Genetic transcription, Genomes, Genomic instability, Genomic Instability - genetics, Genomics, Humans, Hybrids, Ligases, Physiological aspects, Plasmids, R-loops, Replication, Research and analysis methods, RNA, Tetracycline, Tetracyclines, Transcription, Ubiquitin, Ubiquitin-protein ligase, Ubiquitin-Protein Ligases - genetics, Ubiquitin-Protein Ligases - metabolism, Yeast