Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I
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...
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/88392 http://hdl.handle.net/10220/45779 |
| _version_ | 1811682758860210176 |
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| author | Peter, Sabrina Yu, Haojie Ivanyi-Nagy, Roland Dröge, Peter |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Peter, Sabrina Yu, Haojie Ivanyi-Nagy, Roland Dröge, Peter |
| author_sort | Peter, Sabrina |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:01:56Z |
| format | Journal Article |
| id | ntu-10356/88392 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:01:56Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/883922023-02-28T16:56:43Z Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I Peter, Sabrina Yu, Haojie Ivanyi-Nagy, Roland Dröge, Peter School of Biological Sciences Topoisomerase DRNTU::Science::Biological sciences HMGA2 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. MOE (Min. of Education, S’pore) Published version 2018-08-31T02:25:40Z 2019-12-06T17:02:16Z 2018-08-31T02:25:40Z 2019-12-06T17:02:16Z 2016 Journal Article Peter, S., Yu, H., Ivanyi-Nagy, R., & Dröge, P. (2016). Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I. Nucleic Acids Research, 44(22), e162-. doi:10.1093/nar/gkw759 0305-1048 https://hdl.handle.net/10356/88392 http://hdl.handle.net/10220/45779 10.1093/nar/gkw759 en Nucleic Acids Research © 2016 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 10 p. application/pdf |
| spellingShingle | Topoisomerase DRNTU::Science::Biological sciences HMGA2 Peter, Sabrina Yu, Haojie Ivanyi-Nagy, Roland Dröge, Peter Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I |
| title | Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I |
| title_full | Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I |
| title_fullStr | Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I |
| title_full_unstemmed | Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I |
| title_short | Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I |
| title_sort | cell based high throughput compound screening reveals functional interaction between oncofetal hmga2 and topoisomerase i |
| topic | Topoisomerase DRNTU::Science::Biological sciences HMGA2 |
| url | https://hdl.handle.net/10356/88392 http://hdl.handle.net/10220/45779 |
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