Tethering by lamin A stabilizes and targets the ING1 tumour suppressor

ING proteins interact with core histones through their plant homeodomains (PHDs)(1-4) and with histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes to alter chromatin structure(5-7). Here we identify a lamin interaction domain (LID) found only in ING proteins, through which they bind to and colocalize with lamin A. Lamin knockout (LMNA(-/-)) cells show reduced levels of ING1 that mislocalize. Ectopic lamin A expression increases ING1 levels and re-targets it to the nucleus to act as an epigenetic regulator(6,8). ING1 lacking the LID does not interact with lamin A or affect apoptosis. In LMNA-/- cells, apoptosis is not affected by ING1. Mutation of lamin A results in several laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), a severe premature ageing disorder(9). HGPS cells have reduced ING1 levels that mislocalize. Expression of LID peptides to block lamin A-ING1 interaction induces phenotypes reminiscent of laminopathies including HGPS(9,10). These data show that targeting of ING1 to the nucleus by lamin A maintains ING1 levels and biological function. Known roles for ING proteins in regulating apoptosis and chromatin structure indicate that loss of lamin A-ING interaction may be an effector of lamin A loss, contributing to the HGPS phenotype.