The integrity of the genome in higher eukaryotes, as well as the modulation of its complex structure and functions, is exquisitely regulated. This genomic regulation occurs as a function of time in a very sophisticated and elaborate biological process called cell cycle progression, resulting in cell division, and is also controlled by a highly coordinated and intricate network of molecular signaling pathways, which in turn orchestrate very specific macromolecular interactions among nuclear proteins and DNA at the biochemical level. Among the latter, a prominent enzymatic cycle that is involved in maintaining the integrity of mammalian chromosomes is covalent protein-poly[adenosine diphosphate (ADP)–ribosyl]ation. The importance of this posttranslational modification is illustrated by the close cooperation between two "guardian angels" of the genome, one constitutive and one inducible protein, namely poly(ADP-ribose) polymerase–1 (PARP-1) and p53, and the integration of these pivotal signaling processes with genomic maintenance.