Genotoxic Agents Promote the Nuclear Accumulation of Annexin A2: Role of Annexin A2 in Mitigating DNA Damage

Abstract

Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H2O2), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2′-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.

Annexin A2 Heterotetramer: Structure and Function

“…We have recently shown that the nuclear accumulation of the annexin A2 monomer plays a role in protecting the cells from DNA damage during oxidative stress [105]. Rapid nuclear accumulation of annexin A2 occurred in response to DNA damaging agents such as gamma radiation, UV radiation, chromium VI, and etoposide and under conditions of H 2 O 2 - mediated oxidative stress.…”

Annexin A2 Reduces PCSK9 Protein Levels via a Translational Mechanism and Interacts with the M1 and M2 Domains of PCSK9

“…The protein is present as a monomer and as a heterotetrameric complex with p11 (27) that regulates various cellular processes. AnxA2 is localized in the nucleus (28), in the cytosol, and at the cell membrane. This multifunctional protein, which is mostly implicated in vascular fibrinolysis/homeostasis in endothelial cells (27), binds the CHRD of PCSK9 at the cell surface and inhibits its extracellular LDLR-degrading activity.…”

S100A10: A Key Regulator of Fibrinolysis

“…Following increased ROS levels as a result of treatment with genotoxic agents, annexin A2 accumulates in the nucleus. Increased nuclear annexin A2 levels protected the cells from DNA damage following treatment with various genotoxic agents [113]. Elevated levels of annexin A2, through its redox functions, may therefore protect cancer cells from chemotherapeutic treatment.…”