ATM (Ataxia-telangiectasia mutated) and ATR (ATM- and Rad3-related), members of phosphatidyl inositol 3-kinase-like kinase (PIKK) family, are activated in response to DNA damage. ATM is primarily activated in response to double-strand breaks (DSBs) induced by ionizing radiation and radiomimetic drugs, while ATR acts in response to UV damage. ATR is reported to bind to UV-damaged DNA with greater affinity than to undamaged DNA. Also, damaged DNA stimulates the ATR kinase activity to a significantly higher level than does undamaged DNA. ATM and ATR are usually found localized near the damaged regions within several minutes indicting that these two kinases may also have a damage-sensing role.
After their recruitment to sites of DNA damage, ATM and ATR phosphorylate several intracellular substrates, including Chk1 and Chk2 that in turn target other proteins to induce cell-cycle arrest and allow DNA repair to proceed. In normal cells ATM is present as inert dimers or multimers, which dissociate into highly active ATM monomers following any DNA damage. During this process, ATM undergoes autophosphorylation on Ser1981 and the activated ATM undergoes additional phosphorylations and acetylation reactions. It is believed that after rapid activation of ATM and subsequent phosphorylation of its substrates, ATR is independently activated and maintains phosphorylation of these substrates.
Defects in ATM/ATR signaling pathways are commonly seen in human cancer cells and affect the sensitivity of tumors to DNA-damaging chemo- and radiation therapies. In addition, most cancer cells have defective checkpoints that allow the cell cycle to proceed even in the presence of DSBs caused by ionizing radiation and radiomimetic drugs. Hence, designing drugs that block ATM and ATR activties might be useful in promoting chemo- and radiation sensitization in checkpoint-deficient cancer cells.
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