Oncofetal HMGA2 attenuates genotoxic damage induced by topoisomerase II target compounds through the regulation of local DNA topology

• Main Authors: Ahmed, Syed Moiz, Dröge, Peter
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2021
• Subjects: Science::Biological sciences; Chemotherapy; DNA Topology
• Online Access: https://hdl.handle.net/10356/146193
• Institution: Nanyang Technological University

Rapidly dividing cells maintain chromatin supercoiling homeostasis via two specialized classes of enzymes, DNA topoisomerase type 1 and 2 (TOP1/2).Several important anticancer drugs perturb this homeostasis by targetingTOP1/2, thereby generating genotoxic DNA damage. Our recent studies indicated that the oncofetal chromatin structuring high-mobility group AT-hook 2 (HMGA2) protein plays an important role as a DNA replication fork chaperone in coping with DNA topological ramifications that occur during replication stress, both genome wide and at fragile sites such as sub-telomeres. Intriguingly, a recent large-scale clinical study identifiedHMGA2expression as a sole predicting marker for relapse and poor clinical outcomes in 350 acute myeloid leukemia (AML) patients receiving combinatorial treatments that targeted TOP2 and replicative DNA synthesis. Here, we demonstrate that HMGA2 significantly enhanced the DNA supercoil relaxation activity of the drug target TOP2A and that this activator function is mechanistically linked to HMGA2’s known ability to constrain DNA supercoils within highly compacted ternary complexes. Furthermore, we show thatHMGA2 significantly reduced genotoxic DNA damage in each tested cancer cell model during treatment with the TOP2A poison etoposide or the catalytic TOP2A inhibitor merbarone. Taken together with the recent clinical data obtained with AML patients targeted with TOP2 poisons, our study suggests a novel mechanism of cancer chemo resistance toward combination therapies administering TOP2 poisons or inhibitors. We therefore strongly argue for the future implementation of trials of HMGA2 expression profiling to stratify patients before finalizing clinical treatment regimes