The regulation of p53 transcriptional activity by hnRNPUL-1 and the DNA damage response induced by a novel chemotherapeutic agent, ALX

Thomas, Anoushka (2013). The regulation of p53 transcriptional activity by hnRNPUL-1 and the DNA damage response induced by a novel chemotherapeutic agent, ALX. University of Birmingham. Ph.D.

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Abstract

The tumour suppressor, p53, is a vital DNA damage response protein and its means of transcriptional regulation are vast. hnRNPUL-1 is a multifunctional protein and previous studies have implicated it in the modulation of p53 transcriptional activity, although this has been rather poorly understood. Results presented here demonstrate that hnRNPUL-1 represses p53 transcriptional activity and negatively regulates p21 levels. This is consistent with the depletion of hnRNPUL-1 leading to an increase in cells arrested in G1/S. Together these results confirm that hnRNPUL-1 acts as a p53 co-repressor with specific cellular targets. Mutations in p53 and other DNA damage response proteins not only often contribute to the onset of tumourigenesis but can also be the cause of drug resistance during treatment. The development of a novel chemotherapeutic agent, Alchemix (ALX), was based on the requirement for effective treatment in the face of resistance mechanisms. Little has been known about the mechanism of action of ALX up to now. Findings here demonstrate that ALX treatment primarily induces an ATR-dependent DNA damage response that occurs specifically in cycling cells and culminates in cell death via mitotic catastrophe. Results also show that the response elicited by ALX requires TOP2α and TOP2β, as well as its alkylating ability, but does not involve ATM, p53, or components of the MMR and FA pathway. Therefore, ALX has the potential to treat tumours that have developed resistance to conventional chemotherapeutic drugs.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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