Poly ADP-ribosylation: a DNA break signal mechanism.
Recent evidence obtained with transgenic knockout mice suggests that the enzyme poly(ADP-ribose)polymerase (PARP) does not play a direct role in DNA break processing. 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. In the present report, we conceptualize the idea that PARP is part of a DNA break signal mechanism. In vitro screening studies revealed the existence of a protein family containing a polymer-binding motif of about 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. Biochemical analyses showed that these sequences are directly targeted by PARP-associated polymers in vitro, and this alters several molecular functions of p53- and MARCKS protein. PARP-deficient knockout mice from transgenic mice were 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-related cytoskeletal dysfunction. The knockout phenotype could be rescued by stable expression of the PARP gene. We propose that PARP-associated polymers may recruit signal proteins to sites of DNA breakage and reprogram their functions.
Althaus
F R
FR
University of Zürich-Tierspital, Institute of Pharmacology and Toxicology, Switzerland.
Kleczkowska
H E
HE
Malanga
M
M
Müntener
C R
CR
Pleschke
J M
JM
Ebner
M
M
Auer
B
B
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000246:Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases