APE2 IS A CRITICAL REGULATOR OF THE DNA DAMAGE RESPONSE TO MAINTAIN GENOME INTEGRITY IN MAMMALIAN CELLS

The maintenance of genome integrity and fidelity is essential for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required for the activation of an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of DDR pathway and what the biological significance of APE2 is in mammalian cells. Here, I provide evidence using mammalian cultured cell lines including human pancreatic cancer cells that APE2 is important for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knock-down (KD) leads to enhanced γH2AX foci and increased micronuclei formation. In addition, a small molecule compound is identified as APE2 inhibitor that specifically compromises the binding of APE2 to ssDNA, its 3′-5′ exonuclease activity, and the defined SSB-induced ATR Chk1 DDR pathway in Xenopus egg extracts. Notably, cell viability assays demonstrate that APE2-KD or APE2 inhibitor sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, APE2 is proposed as a general regulator for DDR pathway in genome integrity maintenance in mammalian cells.