Poly(ADP-ribose) Polymerase

Poly (ADP-ribose) polymerase (PARP) catalyzes the post-translational modification of proteins by the addition of multiple ADP-ribose moieties. PARP transfers ADP-ribose from nicotinamide dinucleotide (NAD) to Glu/Asp residues on the substrate protein, and also polymerizes ADP-ribose to form long/branched chain polymers. Tankyrase proteins also display PARP activity.

PARP-1, one of 5 confirmed PARPs, is the most abundant and highly expressed PARP enzyme. PARP-1 detects and relocates to single strand breaks or nicks in chromosomal DNA. PARP-1 is thought to play an important role in the initiation of the DNA repair pathway, although high levels of activation are also associated with increased apoptosis in response to genotoxic stress. In addition, PARP-1 may also operate downstream of the Raf-MEK-ERK pathway through direct interaction with ERK2 in the nucleus. PARP inhibitors are being developed for use in a number of pathologies including cancer, diabetes, stroke and cardiovascular disease.

Tankyrases 1 and 2 (TNKS1/PARP5A and TNKS2/PARP5B/PARP5C) are proteins with poly(ADP-ribose) polymerase activity. Human tankyrases post-translationally modify multiple proteins involved in processes including maintenance of telomere length, sister telomere association, spindle assembly and trafficking of GLUT4-containing vesicles. Recently tankyrases have been shown to be involved in the Wnt signaling pathway. Tankyrases bind directly to axin, a member of the 'destruction complex' involved in β-catenin degradation. Inhibition of tankyrase stabilizes axin, increases the activity of the destruction complex and promotes degradation of β-catenin. Tankyrases are therefore an attractive target for cancer therapy.

Poly-ADP-ribosylation of histone proteins is also emerging as an important epigenetic regulatory mechanism.

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In normal cells, each stage of the cell cycle is tightly regulated, however in cancer cells many genes and proteins that are involved in the regulation of the cell cycle are mutated or over expressed. This poster summarizes the stages of the cell cycle and DNA repair. It also highlights strategies for enhancing replicative stress in cancer cells to force mitotic catastrophe and cell death.

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Poly (ADP-ribose) polymerase Gene Data