Michael Barry Kastan

Discovered that the p53 protein plays an essential role in preventing cells from entering S- phase in response to genotoxic damage, thereby providing the first insights into the biological function of this critical tumor suppressor gene and establishing the presence of cell cycle checkpoints in mammalian cells. Linked the ATM gene, mutated in the cancer-prone disorder, Ataxia-Telangiectasis, to p53, by showing that ATM is required for optimal p53 activation in response to ionizing radiation. Showed that ATM is a bona fide protein kinase that directly phosphorylates p53, establishing the initial biochemical steps in what is now called the DNA Damage Response (DDR) pathway. Subsequently identified phosphorylation sites and their functional ramifications in several other ATM substrates, many of which are also human cancer susceptibility genes (e.g. NBS1, BRCA1, FANCD2, and SMC1). Elucidated the biochemical mechanism by which the ATM kinase is activated by intermolecular auto-phosphorylation and dimer dissociation to initiate the DDR pathway.