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

Shaun Scaramuzza, Rebecca M. Jones, Martina Muste Sadurni, Alicja Reynolds-Winczura, Divyasree Poovathumkadavil, Abigail Farrell, Toyoaki Natsume, Patricia Rojas, Cyntia Fernandez Cuesta, Masato T. Kanemaki, Marco Saponaro and Agnieszka Gambus ()
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Shaun Scaramuzza: University of Birmingham
Rebecca M. Jones: University of Birmingham
Martina Muste Sadurni: University of Birmingham
Alicja Reynolds-Winczura: University of Birmingham
Divyasree Poovathumkadavil: University of Birmingham
Abigail Farrell: University of Birmingham
Toyoaki Natsume: Research Organization of Information and Systems
Patricia Rojas: University of Birmingham
Cyntia Fernandez Cuesta: University of Birmingham
Masato T. Kanemaki: Research Organization of Information and Systems
Marco Saponaro: University of Birmingham
Agnieszka Gambus: University of Birmingham

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40695-y

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