Role of IFI16 in DNA damage and checkpoint

Abstract

IFI16 is a member of the HIN-200 family (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeat) that contains a DNA binding domain, a transcriptional regulatory domain, DAPIN/PAAD domain associated with interferon (IFN) response and a binding domain for BRCA1, breast cancer tumor suppressor protein. IFI16 has been identified as a target of IFNa and g and is a member of the HIN-200 family. Although series of initial studies have demonstrated a potential activity of IFI16, a physiological role of the protein was largely unknown. A novel insight of the function of IFI16 stemmed from the observation that IFI16 constitutively binds to BRCA1 breast cancer tumor suppressor. Furthermore, it has been demonstrated that IFI16 is involved in p53-mediated regulation of cell growth and apoptosis. Immunocytochemical and immunohistological analyses of breast cancer cell lines and specimens revealed that levels of IFI16 are frequently decreased, supporting the notion that loss of IFI16 is closely associated with tumor development. Finally, siRNA-mediated depletion of IFI16 induces levels of NBS1, nijmegen breakage syndrome protein 1, leading to activation of DNA-PK (DNA-dependent kinase), phosphorylation of p53 Ser37 and accumulation of p21WAF1. Localization of IFI16 is determined by the status of BRCA1 protein under conditions of DNA damage, such as ionizing radiation (IR). More recently, it has been shown that levels of IFI16 are increased by oxidative stress. Together, these results illustrate that IFI16 is involved in DNA damage signaling and cell cycle checkpoint.