Sphingolipids in the DNA damage response

Abstract

Recently, sphingolipid metabolizing enzymes have emerged as important targets of many chemotherapeutics and DNA damaging agents and therefore play significant roles in mediating the physiological response of the cell to DNA damage. In this review we will highlight points of connection between the DNA damage response (DDR) and sphingolipid metabolism; specifically how certain sphingolipid enzymes are regulated in response to DNA damage and how the bioactive lipids produced by these enzymes affect cell fate.

Keywords: Ceramide; DNA damage; Sphingosine; Sphingosine 1-phosphate.

Figure 1

Schematic of the fundamental aspects of the DNA damage response pathway. DNA damage triggers activation of ATM and ATR, which in turn activate p53, CHK1 and CHK2. Activated p53 signals an apoptotic pathway through BAX and caspase-3-mediated PARP cleavage. p53 also signals through p21, cyclin-CDK and RB protein to cause cell cycle arrest. CHK1 and CHK2 can signal through BRCA2 to trigger DNA repair, or through the inhibition of cdc25 to cause cell cycle arrest. CHK1 and CHK2 are also able to activate p53. All signaling events in the DNA damage response ultimately serve to increase genomic stability in the cell.