The Artemis DNA Repair nucleases – from mechanism to therapeutic inhibition
About the research:
Many cancer treatments rely on inducing DNA damage. A conserved family of human DNA repair factors, the metallo-b-lactamase (MBL-fold) enzymes repair this damage. This project will focus on an MBL-fold DNA repair nuclease known as Artemis. Artemis is an excellent target for sensitising tumours to radiation and increasing the efficacy of this very common form of cancer treatment. Moreover, Artemis also is required for cell survival in some tumours that lack the BRCA genes, which control an important alternative DNA repair pathway, meaning that Artemis Inhibitors could act as an effective stand-alone treatment, particularly in BRCA-deficient breast and ovarian cancers, through synthetic lethality.
The work will be underpinned by our extensive preliminary development work on assays and mechanistic studies of MBL-fold enzymes and (metallo)-enzyme inhibition (see references, below). Inhibiting this type of target (DNA repair nucleases) is unprecedented, but with recent developments in the collaborating Schofield lab (Chemistry, Oxford) we are confident in our starting points and that breakthroughs can be achieved during the studentship. We expect that this project will involve both substantial basic research effort to develop assays and define mechanisms of Artemis in the McHugh lab and that this in turn will allow is to identify and refine of small molecules inhibitors in the Schofield lab. The work will therefore address basic questions surrounding the mechanisms of genome maintenance and their relevance to cancer cell survival and provide experience on therapeutic targeting of these cellular mechanisms.
Broad training in cell biology, mammalian cell genetics, genome engineering, biochemistry and protein purification, drug screens and validation, possibility for training in state-of-the-art structural biology methods including cryoEM.
Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition.
Yosaatmadja Y, Baddock HT, Newman JA, Bielinski M, Gavard AE, Mukhopadhyay SMM, Dannerfjord AA, Schofield CJ, McHugh PJ, Gileadi O. Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition. Nucleic Acids Res. 2021 Aug 13: doi: 10.1093/nar/gkab693. Online ahead of print. PMID: 34387696
Baddock HT, Newman JA, Yosaatmadja Y, Bielinski M, Schofield CJ, Gileadi O, McHugh PJ. A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family. Nucleic Acids Res. 2021 Aug 13: doi: 10.1093/nar/gkab692. Online ahead of print. PMID: 34387694