Investigating SETD1A as a novel epigenetic regulator of parp inhibition

Sweatman, Ellie ORCID: 0000-0002-5555-0574 (2025). Investigating SETD1A as a novel epigenetic regulator of parp inhibition. University of Birmingham. Ph.D.

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Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the treatment of BRCA1-deficient tumours and further evidence suggests their efficacy also extends to deficiencies in other genetic factors associated with homologous recombination (HR), including ATM. However, the clinical success of these compounds is hampered by resistance, as well as a lack of good biomarkers to determine which patients are likely to benefit from PARPi treatment. Recent findings identified the lysine methyltransferase SETD1A as a novel factor conferring PARPi resistance in BRCA1-deficient cells by restoring HR. In this thesis I build upon these previous findings to ask if SETD1A contributes to PARPi resistance in ATM-deficient cells and determine the mechanisms responsible.
Clonogenic survival and immunofluorescent DNA repair assays revealed SETD1A knockdown reduced olaparib sensitivity in ATM-deficient cells through partial restoration of HR, driven by abrogation of H3K4 methylation. On the other hand, Cas9-mediated gene editing of SETD1A increased PARPi sensitivity in the absence of ATM, which was attributed to depletion of residual SETD1A protein expression and increased p53 expression. Based on its role as a H3K4 methyltransferase, we performed RNA-sequencing analysis revealing SETD1A-dependent transcription of the crossover junction endonuclease EME1 correlated with olaparib sensitivity. Accordingly, loss of EME1 phenocopied loss of SETD1A, inducing PARPi resistance and restoring HR in BRCA1 or ATM-deficient cells.
In conclusion, loss of SETD1A or EME1 may underlie PARPi resistance in the clinic and their expression or activity could offer potential new biomarkers to predict patient response and improve outcomes following PARPi treatment.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):