The interaction of HMGA2 with Ku80/70 dysregulates DNA-PK signaling: a novel regulatory pathway in response to genotoxic stress by doxorubicin Free

1972

Ku80/70 heterodimers promote nonhomologous end joining (NHEJ) of DNA breaks by complexing with DNA-PKcs and, as shown here, interact with architectural transcription factor HMGA2. Consequently, the interaction of HMGA2 with Ku80/70 leads to accumulation of basal DNA strand breakage and dysregulation of DNA-PK signaling upon exposure of doxorubicin (Dox). We have previously reported the hypersensitivity of HMGA2-expressing cells to Dox, cisplatin and irradiation; however, the detailed mechanism underlying HMGA2-dysregulated DNA damage response remains unclear. In the present study, we first demonstrate that HMGA2-expessing cells display a deficiency in overall and precise end-joining repair and accumulate more endogenous DNA damage prior to Dox-treatment. Second, HMGA2 renders a sustained phosphorylation of DNA-PKcs-Ser-2056/-Thr-2609, perhaps reflecting the lack of proper repair in Dox-treated cells. While HMGA2 potentiates Dox-induced caspase-3 activation and accumulation of p53-Ser-15 phosphorylation, HMGA2 attenuates phosphorylation of ATM-Ser-1981 and Chk2-Thr-86 in response to Dox-exposure. Altogether, DNA-PK signaling and DNA repair are probably uncoupled in HMGA2-expressing cells. Biochemically, both C-terminal region and AT-hooks of HMGA2 are indispensable for the interaction of HMGA2 with Ku80 and the enhancement of Dox-elicited cytotoxicity. Therefore, HMGA2 dysregulates DNA damage-triggered DNA-PK and ATM signaling network, representing a novel regulatory pathway to promote sensitivity to DNA damage.