TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells

• Published in: Nature communications Vol. 14; no. 1; p. 5071
• Main Authors: Scaramuzza, Shaun, Jones, Rebecca M., Sadurni, Martina Muste, Reynolds-Winczura, Alicja, Poovathumkadavil, Divyasree, Farrell, Abigail, Natsume, Toyoaki, Rojas, Patricia, Cuesta, Cyntia Fernandez, Kanemaki, Masato T., Saponaro, Marco, Gambus, Agnieszka
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-08-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 13/89; 14/63; 38/15; 38/23; 38/77; 45; 631/337/1427/2567; 631/337/151/1431; 631/337/458/582; 631/80/641/151/2356; 64; 64/114; Cell Cycle; Cell division; Cell Division - genetics; Cell proliferation; Cell Proliferation - genetics; Cell Survival; Cell viability; Damage prevention; Degradation; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; Dwarfism; Genomes; Humanities and Social Sciences; Humans; Integrity; multidisciplinary; Mutation; Replication; S Phase - genetics; Science; Science (multidisciplinary); Senescence; Transcription; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40695-y

Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We conclude that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.
The TRAIP E3 ubiquitin ligase is essential for genome integrity, mutations lead to primordial dwarfism in patients. Here, the authors show that TRAIP degradation in S-phase, results in cell arrest due to DNA damage caused by replication-transcription conflicts.