Cancer cells experience genomic instability, probably through a combination of excessive replicative activity and the loss of function of checkpoint and DNA repair pathways that may have contributed to the oncogenic transformation. Chemotherapy by DNA-damaging agents such as cisplatin and nitrogen mustards create DNA interstrand crosslinks (ICL), which can lead to double-strand breaks and cell death when the cells replicate their DNA. Genotoxic drugs are counteracted by the cell’s DNA damage response. Hence, it is expected that inhibiting DNA repair proteins would sensitise cells to chemotherapy. Here we address an enzyme that participates in the repair of ICLs, DCLRE1A. The TEP includes expression clones and methods for producing the catalytic domain and high-throughput activity assays. Furthermore, we provide a crystallization system that generates thousands of reproducible crystals that allow soaking of small-molecule ligands. We provide crystal structures of several small molecule fragments and inhibitors, opening the way to development of more potent and selective inhibitors.

This document represents version 3 of the TEP datasheet and includes all updates on the project as of April 2018. For more information about TEPs and the TEP Programme, please visit https://thesgc.org/tep.