Poly(ADP-ribosyl)ation is an immediate cellular response to DNA damage generated either exogenously or endogenously. This post-translational modification is catalyzed by
poly(ADP-ribose) polymerase (PARP, PARP-1, EC 2.4.2.30). It is proposed that this
protein plays a multifunctional role in many cellular processes, including DNA repair, recombination, cell proliferation and death, as well as
genomic stability. Chemical inhibitors of the
enzyme, dominant negative or null mutations of PARP-1 cause a high degree of
genomic instability in cells. Inhibition of PARP activity by chemical inhibitors renders mice or rats susceptible to carcinogenic agents in various
tumor models, indicating a role for PARP-1 in suppressing
tumorigenesis. Despite the above observations, PARP-1 knockout mice are generally not prone to the development of
tumors. An enhanced
tumor development was observed, however, when the PARP-1 null mutation was introduced into severely compromised immune-deficient mice (a mutation in
DNA-dependent protein kinase) or mice lacking other DNA repair or chromosomal guardian molecules, such as p53 or Ku80. These studies indicate that PARP-1 functions as a cofactor to suppress
tumorigenesis via its role in stabilization of the genome, and/or by interacting with other
DNA strand break-sensing molecules. Studies using PARP-1 mutants and chemical inhibitors have started to shed light on the role of this
protein and of the specific
protein post-translational modification in the control of
genomic stability and hence its involvement in
cancer.