Date Published: May 8, 2019
Publisher: Public Library of Science
Author(s): Syed Moiz Ahmed, Priya Dharshana Ramani, Stephen Qi Rong Wong, Xiaodan Zhao, Roland Ivanyi-Nagy, Tang Choong Leong, Clarinda Chua, Zhizhong Li, Hannes Hentze, Iain BeeHuat Tan, Jie Yan, Ramanuj DasGupta, Peter Dröge, Fenfei Leng.
The transient build-up of DNA supercoiling during the translocation of replication forks threatens genome stability and is controlled by DNA topoisomerases (TOPs). This crucial process has been exploited with TOP poisons for cancer chemotherapy. However, pinpointing cellular determinants of the best clinical response to TOP poisons still remains enigmatic. Here, we present an integrated approach and demonstrate that endogenous and exogenous expression of the oncofetal high-mobility group AT-hook 2 (HMGA2) protein exhibited broad protection against the formation of hydroxyurea-induced DNA breaks in various cancer cells, thus corroborating our previously proposed model in which HMGA2 functions as a replication fork chaperone that forms a protective DNA scaffold at or close to stalled replication forks. We now further demonstrate that high levels of HMGA2 also protected cancer cells against DNA breaks triggered by the clinically important TOP1 poison irinotecan. This protection is most likely due to the recently identified DNA supercoil constraining function of HMGA2 in combination with exclusion of TOP1 from binding to supercoiled substrate DNA. In contrast, low to moderate HMGA2 protein levels surprisingly potentiated the formation of irinotecan-induced genotoxic covalent TOP1-DNA cleavage complexes. Our data from cell-based and several in vitro assays indicate that, mechanistically, this potentiating role involves enhanced drug-target interactions mediated by HMGA2 in ternary complexes with supercoiled DNA. Subtelomeric regions were found to be extraordinarily vulnerable to these genotoxic challenges induced by TOP1 poisoning, pointing at strong DNA topological barriers located at human telomeres. These findings were corroborated by an increased irinotecan sensitivity of patient-derived xenografts of colorectal cancers exhibiting low to moderate HMGA2 levels. Collectively, we uncovered a therapeutically important control mechanism of transient changes in chromosomal DNA topology that ultimately leads to enhanced human subtelomere stability.
DNA transactions in all life forms require that protein complexes translocate at high speed along the two intertwined strands of the DNA double helix. If these complexes are not free to rotate around the DNA template, the translocation process will induce changes in local DNA topology. In this context, the introduction of positive (+) and negative (-) DNA supercoiling are the most profound consequences, and the generation of such transient supercoil waves in the chromatin appears to be inevitable [1, 2]. However, under certain conditions, their uncontrolled build-up can also become a threat to genome stability .
The effectiveness of cancer chemotherapy is influenced by several factors, with drug resistance and tumor recurrence as major obstacles to successful therapy. However, the underlying mechanisms that alter this efficacy are not completely understood and vary between patients and tumor types. Our integrated data set uncovers a novel mechanism that implicates HMGA2 as an independent, critical determinant of drug response.