The Return of the INGs, Histone Mark Sensors and Phospholipid Signaling Effectors

Since their discovery, the members of the ING (inhibitor of growth) family of tumor suppressors have emerged as essential and core components of chromatin modifying complexes. Recent work has identified the ING family as histone mark sensors that orchestrate cellular responses to genotoxic insults and regulate chromatin homeostasis. Dysregulation of chromatin homeostasis is implicated in tumorigenesis through mechanisms such as silencing of tumor suppressor genes, inappropriate activation of oncogenes, and genomic instability due to failure to repair DNA damage. This review will concentrate on the chromatin signaling aspects of the ING proteins, focusing on how recognition of histone H3 trimethylated at lysine 4 (H3K4me3) by the PHD (plant homeodomain) finger of ING proteins is critical for regulating cellular functions such as gene expression. We will also discuss how H3K4me3-recognition by ING proteins plays a critical role in their tumor suppressive functions. Finally, we will discuss the relevance of the association between one ING protein (ING2) and the nuclear phosphoinositide, phosphatidylinositol-5-phosphate (PtdIns(5)P). Interestingly, the ING2PtdIns(5)P interaction involves the PHD finger and an adjacent polybasic region. The level of nuclear PtdIns(5)P sharply increases upon genotoxic stress, and this increase positively regulates ING2-mediated responses. Thus, the PHD finger of ING2 integrates phosphoinositide and chromatin signaling networks to prevent unchecked cell growth.