An important goal of our research is to define the signaling pathways downstream of ATM and ATR. One of the approaches that we have taken to identify substrates of these checkpoint kinases uses mass spectrometry. The ATM and ATR kinases preferentially phosphorylate proteins on serines followed by glutamines (SQ). Therefore, one way of identifying potential substrates is to identify proteins that contain phosphorylated SQ motifs. If the phosphorylation of these proteins is regulated by DNA damage then this is a good indication that the protein is an ATM/ATR substrate. Using affinity purification with phospho-SQ antibodies we have purified a number of candidate substrates. One example is the MCM protein complex. The MCM protein complex functions as a helicase to unwind DNA during DNA replication. We showed that at least two subunits of this complex are targets for ATM/ATR phosphorylation. Phosphorylation of the MCM complex may regulate the activity of the helicase in response to DNA damage.