Investigating the relationship between USP50 and WRN in DNA replication

Ellis, Katherine (2024). Investigating the relationship between USP50 and WRN in DNA replication. University of Birmingham. Ph.D.

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Abstract

USP50 is a poorly understood deubiquitinase with emerging roles in replication. Previous work in the laboratory revealed an epistatic relationship between USP50 and the RECQ helicase WRN in preventing replication-associated DNA double-strand breaks. In this thesis we probed the relationship between USP50 and WRN further and examined their shared and independent roles in replication fork progression and restart, DNA double-strand break formation, and response to replication stress. We found that USP50 and WRN co-operate to support fork progression in replicating cells, with USP50 promoting WRN localisation to stalled forks. We found that RECQL4 and RECQL5 rescue DNA replication in cells depleted of USP50 and WRN. We saw that USP50 promotes formation of DNA double-strand breaks near transcription start sites, indicating a novel role in promoting transcription. Investigation of the roles of USP50 and WRN in microsatellite unstable colorectal cancer cells revealed that USP50 is not a synthetic lethal target in these cells, unlike WRN. WRN loss in microsatellite unstable cells leads to loss of D NA damage repair proteins and cell death. Together the data presented in this thesis deepens our understanding of the USP50-WRN relationship in microsatellite stable and unstable cancer cells, and reveals the surprising ability of RECQ helicases to compensate for each other in DNA replication.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):