ING1 (inhibitor of growth family, member 1)

	Figure1. Chromosomal localization of the ING1 gene in Homo sapiens. Figure 2. Structure and transcripts of Human ING1 genes. Coding regions are in dark blue and non-coding regions are represented in light blue. For ING1c v2 and v5: Exons E1d and E1balt (alternative) are represented in yellow. They both code for the same protein: ING1c (Figure 3).
Description	In 1996 Karl Riabowol's group identified a new Tumor Suppressor Gene (TSG) by using subtractive hybridization between cDNAs from normal mammary epithelial cells and mammary epithelial cells from tumor (breast cancer cell-lines). This experiment was followed by an in vivo screen for tumourigenesis. Using this method, the authors identified a new candidate TSG they named ING1 for INhibitor of Growth 1 (Garkavtsev et al., 1996).
Transcription	The ING1 gene has been mapped to chromosome 13 at locus 13q34 close to the telomeric region (Figure 1). Human ING1 is made of four exons, exon 1a, 1b, 1c, and 2, resulting in five transcribed variants (ING1a, ING1b, ING1c, and ING1d) (Figure 2).
Pseudogene	INGX is the pseudogene of ING1 (He et al., 2005).

Description	The amino acid sequence alignment of human ING proteins revealed several conserved regions in their C-terminal part: a Novel Conserved Region (NCR), a Nuclear Localization Signal (NLS), a Plant Homeo Domain (PHD) and a PolyBasic Region (PBR). The ING proteins are characterized by the presence of a highly conserved PHD in their C-terminal part. This domain is commonly found in proteins involved in chromatin modification (Bienz, 2006; Mellor, 2006). In the N-terminal part of ING1b isoform, which is the most abundant isoform with ING1a, there is also a PCNA Interacting Protein motif (PIP) and Partial Bromo Domain (PBD) (Figure 3).
	Figure 3. Schematic representation of ING1 proteins structure. In the C-terminal part: Novel Conserved Region (NCR), Nuclear Localization Signal (NLS), Plant Homeo Domain (PHD) and PolyBasic Region (PBR). In the N-terminal part of p33ING1b: PCNA Interacting Protein motif (PIP) and Partial Bromo Domain (PBD).
Expression	ING1 is ubiquitously expressed in mammalian tissues (Walzak et al., 2008).
Localisation	The ING1 protein contains an NLS domain, so it is mainly located in the nucleus. Members of the 14-3-3 family are able to interact with ING1 phosphorylated on serine 199 leading to its relocalisation to the cytoplasm (Gong et al., 2006). Recently, it has been found that ING1b translocates also into mitochondria after UV or IR. This translocation is independent of p53 (Bose et al., 2013).
Function	ING1 has been identified as a tumor suppressor gene with Gatekeepers and Caretakers functions. Initially ING1 has been characterized as gatekeeper genes which are known to regulate the growth of tumors through senescence, apoptosis and cell cycle regulation. Indeed, ING1 is involved in the regulation of the cell cycle arrest, apoptosis and senescence. Firtsly, ING1b has been described to physically interact with the tumor suppressor protein p53 and being necessary for its transcriptional activity (Garkavtsev et al., 1998). ING1 is also involved in the regulation of p53 activity. Under stress, ING1b interact with PI5P in order to activate the p300 acetylase which acetylates p53 on lysine 382. This acetylation promotes the transcription of factors involved in cell cycle arrest, senescence and apoptosis (p21, Bax) (Garkavtsev et al., 1998; Kataoka et al., 2003). ING1b is also able to interact with SIRT1, a histone deacetylase known for the p53 deacetylation. SIRT1 interaction with ING1b competitively inhibits its interaction with p53 leading to the maintenance of p53 activity (Kataoka et al., 2003). Moreover, ING1b is known to stabilize p53 by disrupting the regulation of p53 by MDM2 (Leung et al., 2002). ING1 functions can also be independent of p53 signaling pathways. ING1 has been described to interact with the Sin3/HDAC1/HDAC2/SAP30 complex through a direct interaction with SAP30 (Kuzmichev et al., 2002). ING1b has also been reported to increase the expression of Heat Shock Protein 70 (HSP70). This induction of HSP70 required the amino terminus of ING1b but not the PHD, PBR and NLS region (Feng et al., 2006). HSP70 is known to inhibit the NF-kB pathways (Ran et al., 2004; Shi et al., 2006). More recently, it has been shown that the C-terminal PHD of ING1 interacts with histone H3 trimethylated at Lys4 (H3K4me3). This interaction is involved in DNA repair and apoptotic activities of ING1 (Peña et al., 2008). Under stress, ING1 interaction with H3K4me4 leads to the recruitment of the Sin3/HDAC1-2/SAP30 transcriptional repressor complex. Under UV stress, ING1b targets the nucleolus and stabilizes Cellular Senescence-Inhibited Gene (CSIG) through its Nucleolar Targeting Signal (NTS). This interaction is required for ING1b dependent apoptosis after UV stress (Li et al., 2012). More recently, ING1 has been characterized as a caretaker gene which controls the integrity of the genome. Indeed, ING1b is involved in DNA repair in response to UV. ING1b overexpression has been described to enhance repair of UV-damaged DNA in a p53 dependent manner. Furthermore, binding between ING1b and Growth Arrest and DNA Damage 45 (GADD45) has been reported. These findings suggest that ING1b cooperates with GADD45 and p53 in Nucleotide Excision Repair (NER) (Cheung Jr. et al., 2001). Interestingly, ING1b is also required for PCNA monoubiquitination in response to UV. More precisely, ING1b is necessary for the loading of the E3 ubiquitin ligase Rad18 at stalled replication forks through histone H4 acetylation (Wong et al., 2011).
	Figure 4. Schematic representation of ING1 functions. Modified from Guérillon et al., 2013.
Homology	The C-terminal part of ING proteins is highly-conserved through human to plant, especially the PHD-finger motif. There are five human ING genes (ING1, ING2, ING3, ING4, and ING5) which encode multiple isoforms via splicing.

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