Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes
Fig 7
Current model for the formation and repair of DNA damage following FEN1 inhibition.
The inhibition of FEN1 leads to the accumulation of immature Okazaki fragments bound by RPA, accumulating aberrant replication structures that destabilise the replication fork. The PRR machinery is thought to allow for the tolerance of such structures by switching template strand, however failure to do so in a timely manner could lead to the stalling and, ultimately, collapse of the fork. The broken fork would require processing by endonucleases to create a 3’ overhang able to invade into back into the dsDNA and re-start replication. Persistent inhibition of FEN1 would ultimately lead to an overwhelming level of DNA damage and, ultimately, cell death.