Chaperoning HMGA2 Protein Protects Stalled Replication Forks in Stem and Cancer Cells

Yu, Haojie; Lim, Hong Hwa; Tjokro, Natalia; Sathiyanathan, Padmapriya; Natarajan, Suchitra; Chew, Tian Wei; Klonisch, Thomas; Goodman, Steven D.; Surana, Uttam; Dröge, Peter

doi:10.1016/j.celrep.2014.01.014

Cited by 41 publications

(114 citation statements)

References 69 publications

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“…Expression vectors for wild-type HMGA2, the 23M mutant and HMGA1a/1b were described in (18). Expression vectors for the 123M and the linker 1 deletion mutant were generated by site-directed mutagenesis (Agilent Technologies), using vectors for 23M and wild-type HMGA2 as templates, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…DNA-binding is also critical locally for modulation of gene expression in the context of cell differentiation/transformation processes (11,15,16). Furthermore, we have shown that HMGA2 protects cancer cells from DNA damage induced by chemotherapeutic agents via roles in base excision repair (17) and chaperoning of stalled DNA replication forks (18). Both functions require functional AT-hooks for DNA-binding.…”

Section: Introductionmentioning

confidence: 99%

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Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I

Peter¹,

Yu²,

Ivanyi‐Nagy³

et al. 2016

Nucleic Acids Res

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HMGA2 is an important chromatin factor that interacts with DNA via three AT-hook domains, thereby regulating chromatin architecture and transcription during embryonic and fetal development. The protein is absent from differentiated somatic cells, but aberrantly re-expressed in most aggressive human neoplasias where it is causally linked to cell transformation and metastasis. DNA-binding also enables HMGA2 to protect cancer cells from DNA-damaging agents. HMGA2 therefore is considered to be a prime drug target for many aggressive malignancies. Here, we have developed a broadly applicable cell-based reporter system which can identify HMGA2 antagonists targeting functionally important protein domains, as validated with the known AT-hook competitor netropsin. In addition, high-throughput screening can uncover functional links between HMGA2 and cellular factors important for cell transformation. This is demonstrated with the discovery that HMGA2 potentiates the clinically important topoisomerase I inhibitor irinotecan/SN-38 in trapping the enzyme in covalent DNA-complexes, thereby attenuating transcription.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I

Peter¹,

Yu²,

Ivanyi‐Nagy³

et al. 2016

Nucleic Acids Res

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“…The human pituitary tumor transforming gene (PTTG) is highly expressed in human thyroid carcinoma and binds to and inhibits Ku70 protein. Suppression of PTTG gene expression coincides with an up-regulation of DNA repair proteins in thyroid cancer suggesting a role for PTTG in therapeutic resistance (41–45). XRCC7 is another NHEJ factor and XRCC7 Ile3434Thr polymorphism has recently been associated with increased incidence of DTC (46).…”

Section: Mechanisms Of Therapy Resistance In Thyroid Cancermentioning

confidence: 99%

“…Recently, we showed that HMGA2 plays an important novel role in protecting the integrity and functionality of arrested replication forks in cancer cells. HMGA2 preferentially binds with higher affinity to DNA Y- (replication fork) and X- (Holliday junctions) structures typically observed at replication forks (45). Binding of HMGA2 to these DNA conformations protected stalled replication forks from endonuclease digestion and conferred a survival advantage onto HMGA2 + cancer cells, including thyroid cancer cells, when exposed to chemotherapeutics such as hydroxyurea used in the treatment of cancer patients (45).…”

Section: High-mobility Group A2: a Link Between Stemness Emt And Chmentioning

confidence: 99%

Mechanisms of Therapeutic Resistance in Cancer (Stem) Cells with Emphasis on Thyroid Cancer Cells

et al. 2014

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The two main reasons for death of cancer patients, tumor recurrence and metastasis, are multi-stage cellular processes that involve increased cell plasticity and coincide with elevated resistance to anti-cancer treatments. Epithelial-to-mesenchymal transition (EMT) is a key contributor to metastasis in many cancer types, including thyroid cancer and is known to confer stem cell-like properties onto cancer cells. This review provides an overview of molecular mechanisms and factors known to contribute to cancer cell plasticity and capable of enhancing cancer cell resistance to radio- and chemotherapy. We elucidate the role of DNA repair mechanisms in contributing to therapeutic resistance, with a special emphasis on thyroid cancer. Next, we explore the emerging roles of autophagy and damage-associated molecular pattern responses in EMT and chemoresistance in tumor cells. Finally, we demonstrate how cancer cells, including thyroid cancer cells, can highjack the oncofetal nucleoprotein high-mobility group A2 to gain increased transformative cell plasticity, prevent apoptosis, and enhance metastasis of chemoresistant tumor cells.

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“…Besides important regulatory roles in gene expression, in particular during embryonic/fetal development and tumorigenesis/metastasis in the adult organism (Droge and Davey, ; Fusco and Fedele, ; Pfannkuche et al , ; Sgarra et al , ), HMGA2 has also been implicated in DNA base excision repair (Summer et al , ) and DNA damage repair signaling pathways (Hombach‐Klonisch et al , ; Natarajan et al , ; Palmieri et al , ), hinting at important functions for HMGA2 in genome stability following genotoxic stress conditions. In this context, fast proliferation rates of cancer cells enhance DNA replication stress (Gaillard et al , ), and we have recently demonstrated that HMGA2 broadly protects hydroxyurea (HU)‐induced stalled replication forks from collapse into genotoxic DSBs in human cancer and stem cells, thus implying that HMGA2 is also involved upstream of DNA repair processes as a first line of defense to prevent genome instability (Ahmed et al , ; Yu et al , ).…”

Section: Introductionmentioning

confidence: 99%

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

Ahmed

Dröge

2019

Molecular Oncology

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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 targeting TOP1/2, 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 genomewide and at fragile sites such as subtelomeres. Intriguingly, a recent large‐scale clinical study identified HMGA2 expression 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 that HMGA2 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 chemoresistance 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.

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Chaperoning HMGA2 Protein Protects Stalled Replication Forks in Stem and Cancer Cells

Cited by 41 publications

References 69 publications

Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I

Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I

Mechanisms of Therapeutic Resistance in Cancer (Stem) Cells with Emphasis on Thyroid Cancer Cells

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

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