A different kind of ATM
University of Cambridge team explores the role that ATM mutations play in a rare neurodegenerative disease and in cancer drug sensitivity
CAMBRIDGE, U.K.—Genetic mutations are the cause of a variety of diseases and conditions, from Huntington's disease to cancer, and in some cases, mutations in one gene can be tied to more than one condition. That is the case for the ATM gene, which, when mutated, causes the neurodegenerative disease ataxia-telangiectasia (A-T) and is linked to different types of cancer. In addition, mutations in the ATM gene can lead to hypersensitivity to certain DNA-damaging chemotherapeutic agents. In recent work, a team of scientists out of The Gurdon Institute at the University of Cambridge, together with researchers from AstraZeneca, further explored this gene—work that could not only shed light on A-T, but also on the issue of cancer drug resistance. Their results were published in Nature Communications in a paper titled “ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.”
The ATM protein, which is coded for by the ATM gene, operates as something of a watchdog in the genome by detecting and encouraging the repair of DNA damage. Cells that are deficient in ATM present with hypersensitivity to endogenous DNA lesions, which can result in neurodegeneration. Additionally, as noted in the Nature Communications paper, “Similar to loss of function of breast cancer susceptibility genes BRCA1 or BRCA2, ATM loss or mutation causes hypersensitivity to various clinical DNA-damaging agents,” such as PARP inhibitors.
One of the things the teams explored was whether alterations in other genes could affect the drug sensitivity of ATM-deficient cells. Using CRISPR/Cas9 genetic screens, the researchers proved that defects in the products of several other DNA repair genes—among them the BRCA1-A complex and non-homologous end joining factors LIG4, XRCC4 and XLF—can reduce hypersensitivity to cancer drugs such as PARP inhibitors and topotecan, a chemotherapeutic drug.
According to the authors, “Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib reflects delayed engagement of homologous recombination at DNA-replication-fork associated single-ended double-strand breaks (DSBs), allowing some to be subject to toxic NHEJ. Preventing DSB ligation by NHEJ, or enhancing homologous recombination by BRCA1-A complex disruption, suppresses this toxicity, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions.
“Notably, suppressor mutations in ATM-mutant backgrounds are different to those in BRCA1-mutant scenarios, suggesting new opportunities for patient stratification and additional therapeutic vulnerabilities for clinical exploitation.”
Dr. Josep Forment, oncology team leader at AstraZeneca and co-lead/co-corresponding author of the study, said “It has been wonderful collaborating with the group of Prof. Steve Jackson to carry out these exciting studies. My colleagues and I at AstraZeneca are now exploring how these findings might lead to the discovery of more effective cancer treatments.”
Along those lines, the authors pointed out that “Intrinsic or acquired tumor cell resistance to established chemotherapeutics, and towards newer molecularly targeted agents such as PARP inhibitors, is a major problem in cancer management. Understanding the molecular bases for drug resistance is thus crucial in order to establish better patient stratification and combination chemotherapy regimens, as well as to better understand mechanisms and relationships between cellular DDR and other processes … These findings highlight the potential for exploiting a resistance mechanism towards one drug type as a sensitization mechanism towards another therapeutic regime, through a process of acquired vulnerability.”
Prof. Steve Jackson of The Gurdon Institute, co-corresponding author for this recent work, commented that "This study marks a major step forward in our understanding of how the ATM protein maintains genome stability and how ATM defects can cause cancer and neurodegeneration in human patients with A-T. My colleagues and I are very excited by the potential clinical applications for our findings, which we now plan to actively pursue in my laboratory and with our colleagues elsewhere."
Jackson's lab, as noted on The Gurdon Institute's website, is exploring DNA damage and the “maintenance of genomic stability,” with a focus on “the cell biology and mechanisms of established DDR [DNA damage response] pathways, and to apply this knowledge to better understand and treat human diseases. We are also developing approaches to identify new DDR components and their functions … With colleagues at the MRC Epidemiology Unit, Cambridge, we identified genetic variants associated with Y chromosome loss, with implications for genome instability and cancer susceptibility. Finally, we are using CRISPR-Cas9 synthetic viability screens to identify novel DDR proteins and define drug-resistance mechanisms.”