Tej K. Pandita, Ph.D.

DEPARTMENT OF Radiation Oncology
Keywords: radiation signaling, histone code, DNA damage response, telomere, ATM

Radiation genetics, and radiation biology tries 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 optimise cell survival following DNA damage. The goal of our research is to characterize the critical factor(s) that maintain genome stability after IR exposure. DNA damage response involves the actions of DNA repair proteins together with the 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 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 cellular responses to IR, as cells lacking ATM are radiosensitive. We have shown that the ATM gene product is involved in DNA double strand break (DSB) repair as well as telomere metabolism. We identified a chromatin-modifying factor "hMOF"; which interacts with ATM. hMOF, has histone acetyltransferase activity and acetylates histone H4K16. Inactivation of hMOF results in abrogation of ATM function. Based on the fact that hMOF 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 are focused to reveal whether IR exposure influences the acetylation of histone H4 at K16 by MOF and how such chromatin modification plays 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 plan to determine whether HP1 beta deficiency influences DDR.