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

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.

Senescence-Related Diagnostic Biomarkers in Gastric Carcinoma: Identification and Comprehensive Analysis Using a Machine Learning Algorithm

“…10A). Conversely, the low-risk group exhibited enrichment in gene sets associated with cell cycle (22), DNA replication (23), glycerolipid metabolism (24), ribosomes (25), and spliceosomes(26) (Fig. 10B), all of which are associated with senescence.…”

A Decade of Discovery—Eukaryotic Replisome Disassembly at Replication Termination

“…As well as being involved in ICL repair, TRAIP has also been found to help resolve DNA damage and replication stress in S-phase caused by a number of factors: UV radiation, which produces pyrimidine dimers and DSBs, hydroxyurea, which creates stalled replication forks, laser-induced DNA damage and endogenous damage caused by replicationtranscription collisions [109][110][111][112]. In unperturbed conditions, TRAIP localises to the nucleoli and this localisation is dependent upon its catalytic activity [111].…”