Cellular and biological aging, oncology KR’s research focuses on the biology, biochemistry and molecular biology of cancer and aging. We focus on understanding the roles of epigenetic regulators, tumour suppressors and telomeres in enforcing growth regulation on normal cells and in contributing to the normal cell aging (senescence) program. We reported that the p53 tumour suppressor is activated in senescing primary human fibroblasts and based on this observation, designed a screen with which we discovered the first member of the INhibitor of Growth (ING) family of epigenetic type II tumour suppressors.
Major efforts in our lab are directed towards understanding the biology of the INGs, and in determining factors involved with transmission of the telomere-initiated senescence signal to cell cycle control machinery. The ING proteins function as the targeting modules of HAT and HDAC complexes, interacting specifically with the H3K4Me3 mark through their PHD forms of zinc finger.
ING proteins also interact specifically with lamin A through their lamin interaction domains (LID) that we defined, and have been inplicated in transducing the phenotype of the Hutchinson-Gilford Progeria Syndrome (HGPS) form of segmental accelerated aging. In addition to HGPS, we found that knockdown of ING1 extends cell replicative lifespan to a similar degree that p53 knockdown does, and that the levels of the ING1a isoform of ING1 increases ~10-fold in senencent human fibroblasts. This is more than a consequence of senescence since overexpression of the same isoform by ~10-fold induces senescence in cells via the p16/Rb tumour suppressor axis in 36 hours, and shows many more indices of replicative senescence than other forms of stress-induced senescence. Our ongoing studies are currently focussed on examining the epigenetic regulators that change with, and may be responsible for inducing different aspects of cell senescence, including in the devastating HGPS form of biological aging.
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