Abstract
Exposure to anti-cancer drug or irradiation in cell produces DNA damage. The cellular response to DNA damage induces cell cycle arrest, DNA repair, or apoptosis, called DNA damage response. The central player in DNA damage response is ATM. DNA damage activates ATM and transduces the signal to downstream effectors. Not only outer side genotoxic stresses, cells constantly suffer DNA damage caused by such as free oxygen radicals or unscheduled replication induced by aberrant oncogene activation. Cellular DNA in cells under constant DNA damaging stress always carries the risk of mutation. We revealed DNA damage response pathway is activated in cells in MDS. Activation of DNA damage response pathway induces cell cycle arrest and/or apoptosis to cells in MDS stage, which is consistent with clinically observed ineffective hematopoiesis. This activation of DNA damage response works as a cancer barrier to prevent leukemic transformation. Then, disruption of DNA damage check point directly connects to evolution into overt leukemia. Somatic mutations of ATM have been reported in various hematological malignancies. Not only somatic mutation, we reported rare ATM gene SNPs increases the risk of Hodgkin disease and infantile leukemia development. Especially, our experiment suggested that loss of ATM function increases the susceptibility of MLL gene translocation by etoposide treatment. These observations propose that disruption of ATM dependent genome stability surveillance systems is indispensable for development of lymphoid malignancy. Recently it has been elucidated that DNA damage related molecules regulate of cellular homeostasis other than classical DNA damage. We revealed that ATM are involved in transcriptional regulation, and control cellular differentiation, especially adipocyte differentiation. In this symposium, we would like to present cutting edge of DNA damage related molecule and cellular homeostasis associated with cancer development.
