Poly(ADP-ribose) polymerases (PARP) is
enzyme family repairing single or double
DNA strand breaks induced by different
alkylating agents, ionizing- or UV-irradiation as well as by oxidative stress.
Poly(ADP-ribose) polymerase-1 (PARP-1) is the most studied
enzyme involved in a number of pathways including DNA replication and repair, recombination, gene transcription, cell proliferation and death. A positive correlation between the PARP-activity and the life span of different mammalians has been detected. PARP inhibition in vitro with inhibitors of PARP activity (3-aminobenzamide,
nicotinamide,
picolinamide e.t.c.) in cells from wild type or PARP-1(-/-) mice was followed by high
genomic instability (i.e.
aneuploidy, gene amplifications and deletions, micronuclei formation, sister chromatic exchange, cell ploidy and centrosome number increase) and increased sensitivity to
mutagens. Life span reduction, latency period of spontaneous
tumors development shortening and the increase in susceptibility to
carcinogens have been observed in PARP-knockout mice. Treatment with
PARP inhibitors stimulated chemical and radiation
carcinogenesis in animals. The PARP-1(-/-) mice being additionally disrupted in WRN, p53,
DNA-
PKcs or Ku80 genes the promotion of spontaneous
carcinogenesis was observed as compared with a single gene-disrupted mice. Available data suggest a significant role of PARP in maintenance of
genomic stability, preventing of aging and
carcinogenesis.