Cellular Responses to DNA Damage
Background. The biological effects of ionizing radiation, most chemical carcinogens, and many antitumor drugs are dependent upon the ability of these agents to act as electrophiles in the vicinity of DNA (inside broken lines). Chemical carcinogens, for example, are either inherently electrophilic or they are activated to reactive species by cellular enzymes. Electrophiles are also produced intracellularly by normal metabolic processes. Similarly, reactive compounds are produced by inflammatory cells of the immune system.
The reactive intermediates modify DNA, RNA and protein, forming covalent adducts in which the chemical residue is joined to nucleophilic atoms of the constituent nucleotides or amino acids. Adducts within DNA have special significance in view of their potential to force replication or repair errors and thus lead to heritable genetic alterations. The resulting mutations may constitute an important step in the pathway leading to neoplastic transformation.
The work of this laboratory addresses the biochemical mechanisms by which cells respond to specific forms of DNA damage. The rationale of our work stems from the possibility that the DNA adducts caused by DNA damaging agents will be either mutagenic or cytotoxic, or both.
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