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Phosphoproteomic Analysis of DNA Damage Checkpoint Kinase Signaling Reveals Unexpected Links to Actin Cytoskeletal Remodeling, Cell Migration, and Chemoresistance

The DNA damage response (DDR) is a large signaling network that senses chromatin disruption, and activates a wide range of cellular responses including transcriptional changes, cell cycle arrest, recruitment of DNA repair machinery, and induction of apoptosis or senescence if the damage is irreparable. Chemotherapeutic drugs and ionizing radiation initiate two canonical checkpoint kinase cascades mediated by ATR/Chk1 and ATM/Chk2, respectively. In addition to Chk1 and Chk2 signaling, our lab discovered that DNA damage‐induced activation of the p38/MK2 pathway was critical for sustained DNA damage checkpoint maintenance in cells lacking functional p53. MK2, the third checkpoint effector kinase required for proper DDR‐induced cell sycle arrest, shares the same substrate phosphorylation motif with Chk1 and Chk2, whose core motif is LxRxxS*/T*φ (x, amino acids; *, phosphoacceptor; φ, hydrophobic). However, though they share the same core sequence motifs for substrates, the spatial and temporal dynamics of DDR signaling indicate that each of these checkpoint kinases likely has a set of distinct substrates that contribute to the different phenotypic responses.