Understanding and exploiting the cellular responses to radiotherapy to target cancer
The main aim or our research is to understand how genome stability is maintained in response to DNA double-strand breaks (DSBs). Further, we are exploiting our findings to develop novel targeted cancer therapies in the clinic. Determining the mechanisms by which genome stability is maintained in response to DNA damaging agents, such as ionizing radiation, is important for both understanding the normal cellular responses to DNA damage, while also providing insights into how cancer cells may be specifically targeted. We have previously investigated the role of cell-cycle checkpoints in maintaining genome stability in response to a DSB. Moreover, we have shown how the use of cell cycle checkpoint kinase inhibitors can be used to specifically target SETD2-deficient cancers, which has now entered clinical trials. We are currently exploring the impact of radiation on gene expression programmes and how the DNA damage checkpoint machinery regulates these responses.
This project will provide a training opportunity in the fields of molecular genetics, molecular biology and biochemistry, involving a range of methodologies, including CRISPR/Cas9 gene editing, mass spectrometry, and bioinformatics. Through such approaches we hope to better understand the cellular responses to radiation, and further develop biomarkers to predict and exploit these responses in cancer therapy.
- Linda van Bijsterveldt, Samuel Durley, Timothy S Maughan, Timothy C Humphrey (2020) The challenge of combining chemo- and radiotherapy with checkpoint kinase inhibitors. Clin Cancer Res. Nov 30:clincanres.3358.2020. doi: 10.1158/1078-0432.CCR-20-3358.
- Anoushka Davé, Chen-Chun Pai, Samuel C Durley… Timothy C. Humphrey (2020) Homologous Recombination Repair Intermediates Promote Efficient De Novo Telomere Addition at DNA Double-Strand Breaks Nucleic Acids Res Dec 12 PMID: 318283DOI: 10.1093/nar/gkz1109
- Pai CC, Hsu KF, Durley SC,... Humphrey T.C. (2019) An essential role for dNTP homeostasis following CDK-induced replication stress. J Cell Sci 132 (6) March 25 pii: Jcs226969
- Pai, C.C., Kishkevich, A., Deegan R.S…Humphrey, T.C. (2017) Set2 methyltransferase facilitates DNA replication and promotes genotoxic stress responses through MBF-dependent transcription. Cell Reports 20, 2693-2705.#
- Ahrabi S., Sarkar S., Pfister S.X…Humphrey T.C. (2016) A role for human homologous recombination factors in suppressing microhomology-mediated end joining. Nucleic Acids Res. 44, 5743-5757.
- Pfister, S.X., Markkanen, E., Jiang,Y….Humphrey, T.C. (2015) Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28,557-568.