Main Field(s) of Research, Abstract
Recent studies have shown that a variety of stimuli deriving from the environment or originating from within the cell impinge on the machinery that drives the transition through the cell division cycle. Transduction of such signals within cells relies on rapid and reversible post-translational modification of proteins. The goal of our work is to elucidate pathways that are triggered in response to DNA damage and signal to the cell cycle machinery. In particular, two aspects are under scrutiny: (i) the identification and the role of post-translational modifications of proteins involved in DNA synthesis and DNA repair; (ii) the effect of DNA damage on the onset of mitosis.
DNA damage can be caused by exogenous agents, such as inhaled cigarette smoke, ultraviolet light and dietary factors, or may result from endogenous metabolic processes. Failure to detect and correct DNA damage before cell division results in genetic instability observed in cancer cells. To maintain genome stability, a network of proteins has evolved with the function of sensing and repairing DNA damage. Lesion processing and DNA repair are accompanied by the generation of signals that delay the onset of mitosis. This is known as “DNA damage response” or DDR. Curiously, despite DNA the fact that damaging agents pose a threat to the genome, they still represent the treatment of choice in cancer therapy. The rationale for the use of radiation or radiomimetic drugs in therapy was the argument that they eliminate cancer cells by triggering apoptosis. However, this dogma has been recently challenged by studing the behavior of cancers that develop in the human body. The essence of the challenging argument is that solid cancers are unlikely to retain the ability to self-destruct by apoptosis because it is precisely through inactivation of the apoptotic machinery and promotion of aggressive vascularization that cancer cells succeed to recover from latency and are able to form solid tumors. This suggests that radiation and drugs that cause tumor shrinkage in vivo must operate by mechanisms other than apoptosis. Indeed, oncologists and radiation biologists have observed that in tumors undergoing radio- or chemotherapy, cells die when they try to divide and, typically, daughter chromosomes break when they attempt to separate during mitosis. For this reason, significant effort in basic research and drug discovery programs is currently put on the elucidation of DDR pathways and the checkpoints they trigger. It is believed that in the near future, treatment of cancer patients with a combination of tolerable dosages of conventional radio- or chemotherapy and selective drugs that inactivate key cell cycle checkpoints will likely be the avenue to achieve clearance, or at least significant shrinkage, of solid tumors.
Main Field(s) of Research, Keywords
DNA Damage, cell cycle, replication forks
Special Techniques and Equipment
WB, IP assays, Hu treatment