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HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy

HMGA proteins are not translated in normal human somatic cells, but are present in high copy numbers in pluripotent embryonic stem cells and most neoplasias. Correlations between the degree of malignancy, patient prognostic index and HMGA levels have been firmly established. Intriguingly, HMGA2 is a...

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Autores principales: Summer, Heike, Li, Ou, Bao, Qiuye, Zhan, Lihong, Peter, Sabrina, Sathiyanathan, Padmapriya, Henderson, Dana, Klonisch, Thomas, Goodman, Steven D., Dröge, Peter
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715238/
https://www.ncbi.nlm.nih.gov/pubmed/19465398
http://dx.doi.org/10.1093/nar/gkp375
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author Summer, Heike
Li, Ou
Bao, Qiuye
Zhan, Lihong
Peter, Sabrina
Sathiyanathan, Padmapriya
Henderson, Dana
Klonisch, Thomas
Goodman, Steven D.
Dröge, Peter
author_facet Summer, Heike
Li, Ou
Bao, Qiuye
Zhan, Lihong
Peter, Sabrina
Sathiyanathan, Padmapriya
Henderson, Dana
Klonisch, Thomas
Goodman, Steven D.
Dröge, Peter
author_sort Summer, Heike
collection PubMed
description HMGA proteins are not translated in normal human somatic cells, but are present in high copy numbers in pluripotent embryonic stem cells and most neoplasias. Correlations between the degree of malignancy, patient prognostic index and HMGA levels have been firmly established. Intriguingly, HMGA2 is also found in rare tumor-inducing cells which are resistant to chemotherapy. Here, we demonstrate that HMGA1a/b and HMGA2 possess intrinsic dRP and AP site cleavage activities, and that lysines and arginines in the AT-hook DNA-binding domains function as nucleophiles. We also show that HMGA2 can be covalently trapped at genomic abasic sites in cancer cells. By employing a variety of cell-based assays, we provide evidence that the associated lyase activities promote cellular resistance against DNA damage that is targeted by base excision repair (BER) pathways, and that this protection directly correlates with the level of HMGA2 expression. In addition, we demonstrate an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, which supports our conclusion that HMGA2 can be incorporated into the cellular BER machinery. Our study thus identifies an unexpected role for HMGA2 in DNA repair in cancer cells which has important clinical implications for disease diagnosis and therapy.
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spelling pubmed-27152382009-07-24 HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy Summer, Heike Li, Ou Bao, Qiuye Zhan, Lihong Peter, Sabrina Sathiyanathan, Padmapriya Henderson, Dana Klonisch, Thomas Goodman, Steven D. Dröge, Peter Nucleic Acids Res Genome Integrity, Repair and Replication HMGA proteins are not translated in normal human somatic cells, but are present in high copy numbers in pluripotent embryonic stem cells and most neoplasias. Correlations between the degree of malignancy, patient prognostic index and HMGA levels have been firmly established. Intriguingly, HMGA2 is also found in rare tumor-inducing cells which are resistant to chemotherapy. Here, we demonstrate that HMGA1a/b and HMGA2 possess intrinsic dRP and AP site cleavage activities, and that lysines and arginines in the AT-hook DNA-binding domains function as nucleophiles. We also show that HMGA2 can be covalently trapped at genomic abasic sites in cancer cells. By employing a variety of cell-based assays, we provide evidence that the associated lyase activities promote cellular resistance against DNA damage that is targeted by base excision repair (BER) pathways, and that this protection directly correlates with the level of HMGA2 expression. In addition, we demonstrate an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, which supports our conclusion that HMGA2 can be incorporated into the cellular BER machinery. Our study thus identifies an unexpected role for HMGA2 in DNA repair in cancer cells which has important clinical implications for disease diagnosis and therapy. Oxford University Press 2009-07 2009-05-21 /pmc/articles/PMC2715238/ /pubmed/19465398 http://dx.doi.org/10.1093/nar/gkp375 Text en © 2009 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genome Integrity, Repair and Replication
Summer, Heike
Li, Ou
Bao, Qiuye
Zhan, Lihong
Peter, Sabrina
Sathiyanathan, Padmapriya
Henderson, Dana
Klonisch, Thomas
Goodman, Steven D.
Dröge, Peter
HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy
title HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy
title_full HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy
title_fullStr HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy
title_full_unstemmed HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy
title_short HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy
title_sort hmga2 exhibits drp/ap site cleavage activity and protects cancer cells from dna-damage-induced cytotoxicity during chemotherapy
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715238/
https://www.ncbi.nlm.nih.gov/pubmed/19465398
http://dx.doi.org/10.1093/nar/gkp375
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