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 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.
Summer
Heike
H
Division of Genomics and Genetics, School of Biological Sciences, Nanyang Technological University, Singapore.
Li
Ou
O
Bao
Qiuye
Q
Zhan
Lihong
L
Peter
Sabrina
S
Sathiyanathan
Padmapriya
P
Henderson
Dana
D
Klonisch
Thomas
T
Goodman
Steven D
SD
Dröge
Peter
P
D024761:AT-Hook Motifs; D000970:Antineoplastic Agents / Q000633:toxicity*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015894:Genome, Human; D025743:HMGA2 Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000633:toxicity; D008741:Methyl Methanesulfonate / Q000633:toxicity; D009153:Mutagens / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D019761:Phosphorus-Oxygen Lyases / Q000378:metabolism*
D000970:Antineoplastic Agents; D025743:HMGA2 Protein; D009153:Mutagens; D008741:Methyl Methanesulfonate; C423906:5'-deoxyribose phosphate lyase; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D019761:Phosphorus-Oxygen Lyases; D006918:Hydroxyurea