ING Tumor Suppressor Proteins Are Critical Regulators of Chromatin Acetylation Required for Genome Expression and Perpetuation

Abstract

Members of the ING family of tumor suppressors regulate cell cycle progression, apoptosis, and DNA repair as important cofactors of p53. ING1 and ING3 are stable components of the mSin3A HDAC and Tip60/NuA4 HAT complexes, respectively. We now report the purification of the three remaining human ING proteins. While ING2 is in an HDAC complex similar to ING1, ING4 associates with the HBO1 HAT required for normal progression through S phase and the majority of histone H4 acetylation in vivo. ING5 fractionates with two distinct complexes containing HBO1 or nucleosomal H3-specific MOZ/MORF HATs. These ING5 HAT complexes interact with the MCM helicase and are essential for DNA replication to occur during S phase. Our data also indicate that ING subunits are crucial for acetylation of chromatin substrates. Since INGs, HBO1, and MOZ/MORF contribute to oncogenic transformation, the multisubunit assemblies characterized here underscore the critical role of epigenetic regulation in cancer development.

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

“…Other subunits of the complexes are EAF6 (homolog of Esa1-associated factor 6) and BRPF1/2/3 (bromodomain-PHD finger protein 1, 2 or 3) (Figure 2b). Different from MOZ and MORF alone (Champagne et al, 1999;Kitabayashi et al, 2001a), ING5-MOZ/MORF complexes acetylate only histone H3 at lysine 14 (Doyon et al, 2006). Consistent with this, at least BRPF1 stimulates the transcriptional co-activator and HAT activities of MOZ (M Ullah, J Cô te´and XJ Yang, unpublished data), further suggesting that noncatalytic subunits affect the function of MOZ and MORF.…”

“…They were recently found to be stoichiometric subunits of ING5 (inhibitor of growth 5) complexes (Doyon et al, 2006). Other subunits of the complexes are EAF6 (homolog of Esa1-associated factor 6) and BRPF1/2/3 (bromodomain-PHD finger protein 1, 2 or 3) (Figure 2b).…”

Detection of novel mRNA splice variants of human ING4 tumor suppressor gene

“…ING4 has been recently identified as a subunit of HAT complex containing HBO1 (Doyon et al, 2006). We investigated whether this capability is retained by ING4 variants.…”

“…ING proteins are also involved in the regulation of gene expression through localized chromatin modification; this occurs via association of INGs with the HAT and HDAC enzymatic complexes that regulate histone acetylation (Loewith et al, 2000;Gong et al, 2005;Doyon et al, 2006).…”

“…Recently, ING4 protein was found associated to the HAT complex containing HBO1, hEafS and JADE1/2/3 proteins (Zhou et al, 2005;Doyon et al, 2006;Russell et al, 2006). Different mutations in the ING4 transcript were detected in several cancer cell lines, and for all of them a loss of function effect has been proposed.…”