Abstract
The ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT or HDAC complexes and participate in chromatin remodeling that is essential for genomic stability and signaling pathways. The gatekeeper functions of the INGs are well described by their role in the negative regulation of the cell cycle, notably by modulating the stability of p53 or the p300 HAT activity. However, the caretaker functions are described only for ING1, ING2 and ING3. This is due to their involvement in DNA repair such as ING1 that participates not only in NERs after UV-induced damage, but also in DSB repair in which ING2 and ING3 are required for accumulation of ATM, 53BP1 and BRCA1 near the lesion and for the subsequent repair. This review summarizes evidence of the critical roles of ING proteins in cell cycle regulation and DNA repair to maintain genomic stability.
Highlights
The Inhibitor of Growth (ING) gene family was first described in 1996 by the identification of p33ING1 in a study using a strategy based on Genetic Suppressor Elements whose expression promotes tumorigenesis by inhibiting the expression of Tumor Suppressor Genes [1]
High homology has been observed between ING proteins and, their N-terminus domain is unique for each family member, they share a very similar structure since four specific regions are found in the C-terminus of all five ING members: an LZL motif, an NCR, an NLS and a PHD motif (Figure 1)
Since HBO1 and ING5 were reported to participate in the early stages of replication by interacting with ORC1 and MCM helicases, two proteins involved in the pre-replication complex [19], we can hypothesize that the ING5/HBO1 complex keeps the chromatin open
Summary
The Inhibitor of Growth (ING) gene family was first described in 1996 by the identification of p33ING1 in a study using a strategy based on Genetic Suppressor Elements whose expression promotes tumorigenesis by inhibiting the expression of Tumor Suppressor Genes [1]. All ING members harbor a NCR domain which is very specific to this family and whose role is poorly described (the genomic structure of ING was reviewed in [8,9]). Concerning ING2, mRNA levels were found to be downregulated in breast ovarian, lung cancer and hepatocellular carcinoma, whereas ING2 protein was described to be downregulated in melanoma. For all cancers in which they are negatively regulated, ING1 and ING2 protein levels decreased in the nucleus, suggesting a mutation closer to their NLS domain and/or an impaired interaction with a protein required to target ING1 and ING2 to the nucleus. ING4 mRNAs were downregulated in hepatocellular carcinoma, HNSCC and melanoma In the latter two cases, ING4 has been described as negatively regulated at protein levels in astrocytoma, breast cancer and lung cancer. Our work shows that by participating in both the cell cycle and DDR, the INGs are necessary to optimize the relationship and orchestration between these two pathways
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