In response to DNA damage, eukaryotic cells activate ATM-Chk2 and/or ATR-Chk1 to arrest the cell cycle and initiate DNA repair. We show that, in the absence of p53, cells depend on a third cell-cycle checkpoint pathway involving p38MAPK/MK2 for cell-cycle arrest and survival after DNA damage. MK2 depletion in p53-deficient cells, but not in p53 wild-type cells, caused abrogation of the Cdc25A-mediated S phase checkpoint after cisplatin exposure and loss of the Cdc25B-mediated G2/M checkpoint following doxorubicin treatment, resulting in mitotic catastrophe and pronounced regression of murine tumors in vivo. We show that the Chk1 inhibitor UCN-01 also potently inhibits MK2, suggesting that its clinical efficacy results from the simultaneous disruption of two critical checkpoint pathways in p53-defective cells.

SummaryIn response to DNA damage eukaryotic cells activate cell cycle checkpoints -complex kinase signaling networks that prevent further progression through the cell cycle. In parallel to implementing a cell cycle arrest, checkpoint signaling also mediates the recruitment of DNA repair pathways. If the extend of damage exceeds repair capacity, additional signaling cascades are activated to ensure elimination of these damaged cells. The DNA damage response has traditionally been divided into two major kinase branches. The ATM/Chk2 module is activated after DNA double strand breaks and the ATR/Chk1 pathway responds primarily to DNA single strand breaks or bulky lesions. Both pathways converge on Cdc25, a positive regulator of cell cycle progression, which is inhibited by Chk1 or Chk2-mediated phosphorylation. Recently a third effector kinase complex consisting of p38MAPK and MK2 has emerged. This pathway is activated downstream of ATM and ATR in response to DNA damage. MK2 has been shown to share substrate homology with both Chk1 and Chk2. Here we will discuss recent advances in our understanding of the eukaryotic DNA damage response with emphasis on the Chk1, Chk2, and the newly emerged effector kinases p38MAPK and MK2.

Genome instability contributes to cancer development and accelerates age-related pathologies as evidenced by a variety of congenital cancer susceptibility and progeroid syndromes that are caused by defects in genome maintenance mechanisms. DNA damage response (DDR) pathways that are mediated through the tumor suppressor p53 play an important role in the cell-intrinsic responses to genome instability, including a transient cell cycle arrest, senescence and apoptosis. Both senescence and apoptosis are powerful tumor-suppressive pathways preventing the uncontrolled proliferation of transformed cells. However, both pathways can potentially deplete stem and progenitor cell pools, thus promoting tissue degeneration and organ failure, which are both hallmarks of aging. p53 signaling is also involved in mediating non-cell-autonomous interactions with the innate immune system and in the systemic adjustments during the aging process. The network of p53 target genes thus functions as an important regulator of cancer prevention and aging.