Functional Interactions of PARP-1 with p53

Abstract

A close correlation between the frequency of specific mutations of oncogenes and/or tumor suppressor genes in mammals and cancer has been suspected for a long time. For instance, either spontaneous or forcefully inflicted mutations of a tumor suppressor gene coding for a protein known as p53 are usually associated with a variety of malignant tumors. Overwhelming experimental evidence indicates that more than 50% of human neoplasias1 contain one or multiple mutations in one or both alleles of p53. Therefore, the expression product of this pivotal gene, when mutated, appears to play a major role in carcinogenesis. Further significance of p53, as a tumor suppressor protein, is underscored by the fact that over 90% of all tumor-derived mutations associated with it, result in structural and/or functional alterations of its sequence-specific DNA-binding domain2 (Seq-Sp DBD, Fig. 1). Interestingly, the high mutation frequency observed with p53 in malignant tissues initially lead to the misidentification of a mutant of this chromosomal locus as an oncogene rather than its wild type version which functions as the opposite, a tumor suppressor product. An overwhelming amount of work has been done in the last few years to unveil the physiological, biochemical and molecular significance of p53, especially at the protein level. However, in this review the discussion centers on the relevance of the p53 structure and function relationships with poly(ADP-ribose) polymerase-1 (PARP-1), a prominent DNA-strand break sensor in higher eucaryotes, and the biochemical pathway of protein-poly(ADP-ribosyl)ation. A special emphasirity. Therefore, we will present the primary sequence and domain structure of both proteins first.