Nucleic Acids Research Advance Access published online on May 21, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp375
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Genome Integrity, Repair and Replication |
HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy
1Division of Genomics and Genetics, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, 2Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Canada, R3E 0J9 and 3Division of Diagnostic Sciences and Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA
*To whom correspondence should be addressed. Tel: +65 6316 2809; Fax: +65 6791 3856; Email: pdroge{at}ntu.edu.sg
Received January 20, 2009. Revised April 7, 2009. Accepted April 26, 2009.
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.