The long-term goal of our laboratory is to understand how the radiocurability of tumor cells can be enhanced. Combining the disciplines of radiation genetics and radiation biology, we try to understand the relationship between ionizing radiation (IR) sensitivity and genotype (DNA sequence). Signal transduction pathways activated by the DNA damage response (DDR) are the primary determinants of cell survival and transformation. Our research interests are focused on understanding the DDR that has evolved to optimize cell survival following DNA damage. Our major research interest is to characterize the critical factor(s) that maintain genome stability after IR exposure.
The DNA damage response involves the actions of DNA repair proteins together with checkpoint events that slow down or arrest cell-cycle progression while the damage is being removed. Our aim is to determine – at the molecular level – how cells detect IR-induced DNA damage and then trigger the DDR. In the DDR pathway, we are specifically interested in defining the mechanisms by which chromatin modifications function to regulate the cellular response to DNA damaging agents, specifically IR. ATM (ataxia-telangiectasia mutated) appears to be a major regulator of the cellular response to IR, as cells lacking ATM are radiosensitive. We have demonstrated that the ATM gene product is involved in DNA double-strand break (DSB) repair as well as telomere metabolism. We have identified a chromatin-modifying factor "MOF", which interacts with ATM. MOF has histone acetyltransferase activity and acetylates histone H4K16. Inactivation of MOF results in abrogation of ATM function. Based on the fact that MOF is involved in ATM function, one current line of investigation is whether MOF plays an essential role in mammals during embryogenesis and oncogenesis. Our future studies will focus on whether basal acetylation levels of histone H4 at K16 play a role in DDR.
A long-standing question in the DDR field is whether DNA DSB formation affects chromatin condensation. Recent studies have revealed that DSB formation is followed by ATM-dependent chromatin relaxation. ATM's effector in this pathway is KAP-1, which is phosphorylated in an ATM-dependent manner on Ser 824 exclusively at DNA damage sites. KAP-1 recruits HP1 proteins to form small HP1-containing heterochromatin domains that repress gene activity. HP1 has been shown to directly interact with Suv(3)9h1, this interaction may play a key role in the formation of senescence-associated heterochromatin foci (SAHF), which accumulate in nuclei during cellular senescence. We have demonstrated that isoforms of HP1 influence genomic stability, and now plan to determine the mechanistic details how HP1 beta deficiency influences DDR. The ultimate goal is to determine whether such factor/s are involved in sensing IR-induced damage.