Investigating JMJD5 loss of function models to identify and characterise lethal interactions in cancer

Piasecka, Sonia Katarzyna (2025). Investigating JMJD5 loss of function models to identify and characterise lethal interactions in cancer. University of Birmingham. Ph.D.

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Abstract

2-Oxoglutarate (2-OG) Oxygenases are biologically important enzymes involved in both the hydroxylation and demethylation of nucleic acids and proteins. These enigmatic enzymes play important roles in several human diseases, including cancer. JMJD5 is an essential gene that belongs to the ‘JmjC-only’ sub-family of 2-OG oxygenases. It was originally identified as a histone demethylase, but more recent evidence supports its assignment as a protein hydroxylase with complex roles in cancer. JMJD5 has been implicated in a plethora of biological processes, with emerging evidence supporting a role in DNA damage repair (DDR). In this thesis, I have begun to investigate the effect of JMJD5 mutations and loss of function in cancer. We show thatcancer variants impair JMJD5 expression, activity and function in GS. We subsequently
demonstrate that JMJD5 knockdown causes replication stress in tumour cell lines and that this phenotype is dependent on its enzymatic activity. Importantly, we demonstrate that loss of JMJD5 can sensitise cancer cells to various DNA-damaging agents including PARP, ATM and
ATR inhibitors, highlighting its potential as a therapeutic target. Finally, we evaluated the effect of first-in-class inhibitors of JMJD5 on cancer cell lines. We showed that these novel JMJD5 inhibitors decreased cancer cell viability, increased replication stress, and caused cell cycle
perturbations. We also evaluated their ability to sensitise cells to DDR inhibitors and obtained promising results. Overall, our work supports the role of JMJD5 as a promising target for anticancer therapies, particularly in combination with other agents.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):