HMGA2 protects induced pluripotent stem cell chromosomes against hydroxyurea-induced DNA damage.

Abstract

High Motility Group A-T hook 2 (HMGA2) is a transcriptional regulator that binds to short AT rich sequences and is involved in global chromatin reorganization. HMGA2 is normally expressed during early development and is involved in specification of mesoderm-derived tissue. However, HMGA2 is re-expressed in many aggressive neoplasias and correlated with poor patient

outcomes.

Our previous research has shown an involvement of HMGA2 in Base Excision Repair (BER) and in stabilizing stalled replication forks. Cancer cells could hijack these properties of HMGA2 to suppress chromosomal instabilities.

In this study, we use murine induced Pluripotent Stem Cells (iPSC) to investigate whether overexpression of HMGA2 provides protection against DNA damage. The chemotherapeutic Hydroxyurea (HU) was used to disrupt DNA synthesis, create stalled forks and induce DNA damage. Chromosomal

instabilities were investigated via Giemsa staining of metaphase spreads.

Our results clearly show fewer chromosomal aberrations for cells that express exogenous HMGA2 in comparison to the control. We also found overexpression of HMGA2 could increase cell survival at a high HU concentration, and that it reduces the rate of cell proliferation. These results are in excellent agreement with our previous findings and demonstrate a key role for HMGA2 in the cell cycle.