Poly ADP-ribosylation: A DNA break signal mechanism

Recent evidence obtained with transgenic knockout mice suggests that the en zyme poly(ADP-ribose)polymerase (PARP) does not play a direct role in DNA b reak processing [1, 2]. Nevertheless, inactivation of the catalytic or the DNA nick-binding functions of PARP affects cellular responses to genotoxins at the level of cell survival, sister chromatid exchanges and apoptosis [2 , 3]. In the present report, we conceptualize the idea that PARP is part of a DNA break signal mechanism [4, 5]. In vitro screening studies revealed t he existence of a protein family containing a polymer-binding motif of abou t 22 amino acids. This motif is present in p53 protein as well as in MARCKS , a protein involved in the regulation of the actin cytoskeleton. Biochemic al analyses showed that these sequences are directly targeted by PARP-assoc iated polymers in vitro, and this alters several molecular functions of p53 - and MARCKS protein. PARP-deficient knockout mice from transgenic mice wer e found to exhibit several phenotypic features compatible with altered DNA damage signaling, such as downregulation and lack of responsiveness of p53 protein to genotoxins, and morphological changes compatible with MARCKS-rel ated cytoskeletal dysfunction. The knockout phenotype could be rescued by s table expression of the PARP gene. We propose that PARP-associated polymers may recruit signal proteins to sites of DNA breakage and reprogram their f unctions.