The role of poly(ADP-ribose) in the DNA damage signaling network.
DNA damage signaling is crucial for the maintenance of genome integrity. In higher eukaryotes a NAD+-dependent signal transduction mechanism has evolved to protect cells against the genome destabilizing effects of DNA strand breaks. The mechanism involves 2 nuclear enzymes that sense DNA strand breaks, poly(ADP-ribose) polymerase-1 and -2 (PARP-1 and PARP-2). When activated by DNA breaks, these PARPs use NAD+ to catalyze their automodification with negatively charged, long and branched ADP-ribose polymers. Through recruitment of specific proteins at the site of damage and regulation of their activities, these polymers may either directly participate in the repair process or coordinate repair through chromatin unfolding, cell cycle progression, and cell survival-cell death pathways. A number of proteins, including histones, DNA topoisomerases, DNA methyltransferase-1 as well as DNA damage repair and checkpoint proteins (p23, p21, DNA-PK, NF-kB, XRCC1, and others) can be targeted in this manner; the interaction involves a specific poly(ADP-ribose)-binding sequence motif of 20-26 amino acids in the target domains.
Malanga
Maria
M
Institute of Pharmacology and Toxicology, University of Zurich-Tierspital, Switzerland.
Althaus
Felix R
FR
D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D002843:Chromatin / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D008969:Molecular Sequence Data; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002843:Chromatin; D011108:Polymers; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D004264:DNA Topoisomerases, Type I