Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2.
In response to DNA damage eukaryotic cells activate cell cycle checkpoints -- complex kinase signaling networks that prevent further progression through the cell cycle. Parallel to implementing a cell cycle arrest, checkpoint signaling also mediates the recruitment of DNA repair pathways. If the extent 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-mediated 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.
Reinhardt
H Christian
HC
David H Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Yaffe
Michael B
MB
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human