The ING (Inhibitor of Growth) genes have been identified and characterized as candidate tumor suppressor genes. The ING proteins are characterized by their C-terminal region, which is highly conserved from human to plant and contains a Plant HomeoDomain (PHD).
In addition, the C-terminus contains a nuclear localization signal (NLS), which targets INGs to the nucleus. ING proteins are highly conserved during evolution from Yeast to Human. Five ING genes have been identified in human. Our work mainly focuses on ING1, ING2 and ING3 genes. All ING proteins interact with Histone Acetyltransferase (HAT) or histone deacetylase (HDAC) complex to regulate chromatin modifications and gene transcription. ING proteins regulate cell cycle arrest, apoptosis and senescence and thus were first classified as Type II TSG or ‘‘gatekeepers’’.
More recently our work has identified caretaker functions for ING2 (Figure 1) and we have identified SUMO1 modifications as an important translational mechanisms to regulate ING1 and ING2 functions (Figure 2).
Figure 1: ING2 structure and functions. ING2 C-terminal domain contains an NLS, PHD and PBR (PolyBasic Region). The N-terminal domain contains an LZL (Leucin Zipper-Like) motif. Gatekeeper function: ING2 interacts with the Sin3a/HDAC1-HDAC2 complex. Through its affinity with the H3K4Me3 histone mark, ING2 targets the deacetylation complex to the promoter of genes to regulate transcription. Caretaker function: ING2 interacts with PCNA (Proliferating Cell Nuclear Antigen), regulate PCNA amount to the chromatin and control the replication fork progression and genome stability.
Figure 2: SUMO1 modification of ING1 and ING2. ING2 is sumoylated on lysine 195, enhancing its interaction with the Sin3a/HDAC1-HDAC2 complex to regulate transcription of target genes. ING1 is sumoylated on lysine 193 to interact with HIF1α (Hypoxia Inducible Factor α) and regulate its degradation by the proteasome. ING1 sumoylation on lysine 193 is mediated by the E3 SUMO ligase PIAS4 (PIASy) to regulate transcription of target genes.