Mutations in the ATM gene cause the devastating neurodegenerative and cancer predisposition disease ataxia-telangiectasia (A-T), and are also associated with various forms of sporadic cancer. Previous work has shown that the ATM protein, which is produced from the ATM gene, serves as a "molecular guardian of the genome" by detecting DNA damage and promoting its repair. Consequently, A-T patients and ATM-deficient cells are hyper-sensitive to various endogenous DNA lesions that can lead to neurodegeneration, as well as DNA-damaging agents used in cancer therapy such as PARP inhibitors.
In their new publication, researchers in the laboratory of Professor Steve Jackson at the Gurdon Institute collaborated with colleagues at AstraZeneca to identify mechanisms by which the drug sensitivities of ATM-deficient cells can be alleviated through changes in other genes. Thus, using cutting-edge CRISPR-Cas9 genetic screens, the authors show that defects in the products of several genes also involved in DNA repair pathways, including components of the BRCA1-A complex and the non-homologous end joining factors LIG4, XRCC4 and XLF, can alleviate the hypersensitivity of ATM-deficient cells to PARP inhibitors and the chemotherapeutic drug topotecan.
In addition to this work providing new mechanistic insights into how cells respond to DNA damage, these findings also have potential medical relevance. First, they suggest how cancers with ATM mutations might evolve resistance in the clinic and how this may make these resistant cancers susceptible to other anti-cancer agents. Second, they suggest potential therapeutic targets for A-T.
