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SETD1A-dependent EME1 transcription drives PARPi sensitivity in HR deficient tumour cells
Ellie Sweatman1, Rachel Bayley1, Richad Selemane1
1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK.
Background:
Cells deficient in DNA repair factors breast cancer susceptibility 1/2 (BRCA1/2) or ataxia-telangiectasia mutated (ATM) are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Building on our previous findings, we asked how the lysine methyltransferase SETD1A contributed to PARP inhibitor-mediated cell death in these contexts and determined the mechanisms responsible.
Methods:
We used cervical, breast, lung and ovarian cancer cells bearing mutations in BRCA1 or ATM and depleted SETD1A using siRNA or CRISPR/Cas9. We assessed the effects of the PARPi Olaparib on cell viability, homologous recombination, and DNA repair. We assessed underlying transcriptional perturbations using RNAseq. We used The Cancer Genomics Atlas (TCGA) and DepMap to investigate patient survival and cancer cell characteristics.
Results:
Loss of SETD1A from both BRCA1-deficient and ATM-deficient cancer cells was associated with resistance to Olaparib, explained by partial restoration of homologous recombination. Mechanistically, SETD1A-dependent transcription of the crossover junction endonuclease EME1 correlated with sensitivity to Olaparib in these cells. Accordingly, when SETD1A or EME1 was lost, BRCA1 or ATM-mutated cells became resistant to Olaparib, and homologous recombination was partially restored.
Conclusions:
Loss of SETD1A or EME1 drives cellular resistance to Olaparib in certain genetic contexts and may help explain why patients develop resistance to PARP inhibitors in the clinic.
Insights
Loss of SETD1A or EME1 confers resistance to PARP inhibitors like Olaparib in cancer cells with BRCA1 or ATM mutations, potentially explaining clinical resistance to these therapies.
Area of Science:
- Molecular biology
- Cancer genetics
- Drug resistance mechanisms
Background:
- Cells with DNA repair defects (BRCA1/2 or ATM mutations) are sensitive to PARP inhibitors.
- The role of lysine methyltransferase SETD1A in this sensitivity was investigated.
Purpose of the Study:
- To determine how SETD1A influences cell death induced by PARP inhibitors in BRCA1/2 or ATM-deficient cancer cells.
- To elucidate the underlying molecular mechanisms of this influence.
Main Methods:
- Utilized various cancer cell lines (cervical, breast, lung, ovarian) with BRCA1 or ATM mutations.
- Depleted SETD1A using siRNA or CRISPR/Cas9.
- Assessed cell viability, homologous recombination, DNA repair, and transcriptional changes (RNAseq) in response to Olaparib.
- Analyzed patient survival and cancer cell data from TCGA and DepMap.
Main Results:
- Loss of SETD1A in BRCA1- or ATM-deficient cells led to resistance to Olaparib.
- This resistance was linked to a partial restoration of homologous recombination.
- SETD1A-dependent transcription of EME1 correlated with Olaparib sensitivity.
- Loss of SETD1A or EME1 rendered BRCA1/ATM-mutated cells resistant to Olaparib.
Conclusions:
- Loss of SETD1A or EME1 promotes resistance to Olaparib in specific genetic contexts.
- This finding may explain the development of clinical resistance to PARP inhibitors.
