Poly(ADP-ribose) polymerase-1 and ionizing radiation: sensor, signaller and therapeutic target.
Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that binds rapidly to single and double-strand breaks in DNA and consequently modifies a range of nuclear proteins involved in the cellular response to ionising radiation. PARP-1 knockout mice are highly sensitive to ionising radiation, and inhibition or depletion of PARP-1 brings about modest sensitisation of cells in culture to radiation doses of 2 Gy and above. In certain cell lines, chemical inhibition of PARP activity is also associated with marked sensitisation to very low doses of radiation (<0.5 Gy). The mechanisms underlying these effects are discussed, and possible therapeutic applications of PARP-1 manipulation in combination with ionising radiation are considered.
Chalmers
A J
AJ
Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK. chalmers@gci.ac.uk
D000818:Animals; D004260:DNA Repair; D051379:Mice; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000502:physiology*; D011839:Radiation, Ionizing; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D011065:Poly(ADP-ribose) Polymerases