A recently evolved domain of the human ING1 epigenetic regulator targets mitochondria and induces senescence

ING proteins are epigenetic readers, targeting histone acetyl transferase (HAT; ING3-5) or histone deacetylase (HDAC; ING1-2) complexes to modify gene expression. Expression of the ING1a alternatively expressed isoform of ING1 increases markedly with cell age and in response to other exogenous stresses that induce senescence. Overexpression of ING1a rapidly induces cell senescence in human cells by affecting transcription to inhibit endocytosis and activate the retinoblastoma (Rb) cell cycle checkpoint pathway. In this study we detected ING1a expression in several primary and immortalized human cell types, but we were unable to detect ING1a expression in fibroblasts derived from other species. To identify ING1a homologs or orthologs in other species we searched available databases and found that sequences corresponding to the unique region of the ING1a isoform were only found in humans and gorillas, with truncated versions found in orangutans, chimpanzees, mandrills and macaques. In contrast, the ING1b isoform and other ING genes such as ING3-5 are well conserved evolutionarily, including in vascular plants and fungi. ING1a inhibited metabolic activity in numerous primary and established human cells and in Macaca mulatta fibroblasts, but not in murine fibroblasts. The unique amino-terminal region of ING1a we have designated the senescence-associated domain (SAD) targeted ING1a to mitochondria while ING1a missing this sequence was localized exclusively to nucleoli and nuclei and was less effective in inhibing cell cycle progression or inducing senescence-associated beta-galactosidase activity. Considering the natural induction of this isoform as human cells age in culture, expression of ING1a may contribute to limiting the replicative lifespan of cells through altering nuclear transcription, and in a subset of primates, by a distinct mitochondrial mechanism.