The 193-Kd Vault Protein, Vparp, Is a Novel Poly(Adp-Ribose) Polymerase

Abstract

Mammalian vaults are ribonucleoprotein (RNP) complexes, composed of a small ribonucleic acid and three proteins of 100, 193, and 240 kD in size. The 100-kD major vault protein (MVP) accounts for >70% of the particle mass. We have identified the 193-kD vault protein by its interaction with the MVP in a yeast two-hybrid screen and confirmed its identity by peptide sequence analysis. Analysis of the protein sequence revealed a region of ∼350 amino acids that shares 28% identity with the catalytic domain of poly(ADP-ribose) polymerase (PARP). PARP is a nuclear protein that catalyzes the formation of ADP-ribose polymers in response to DNA damage. The catalytic domain of p193 was expressed and purified from bacterial extracts. Like PARP, this domain is capable of catalyzing a poly(ADP-ribosyl)ation reaction; thus, the 193-kD protein is a new PARP. Purified vaults also contain the poly(ADP-ribosyl)ation activity, indicating that the assembled particle retains enzymatic activity. Furthermore, we show that one substrate for this vault-associated PARP activity is the MVP. Immunofluorescence and biochemical data reveal that p193 protein is not entirely associated with the vault particle, suggesting that it may interact with other protein(s). A portion of p193 is nuclear and localizes to the mitotic spindle.

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

“…PARylating ARTDs (pARTDs; ARTD1-6), most prominently ARTD1, have been the focus of cancer related research during the past two decades. Due to their sequence and structural similarity ARTD3 and ARTD4 are classified here as pARTDs, although their ability to form PAR chains is not well established and they have also been postulated to be mARTDs (Kickhoefer et al, 1999;Loseva et al, 2010;). An ARTD inhibitor, Olaparib, has been approved to treat ovarian cancer with BRCA mutations.…”

PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation

“…Tankyrase-1 and -2 are involved in telomere maintenance and possess additional poorly defined functions in the cytoplasm (Smith et al, 1998;Chi and Lodish, 2000;Smith and de Lange, 2000;Lyons et al, 2001;Cook et al, 2002;Sbodio et al, 2002). VPARP is a major component of vaults, cytoplasmic ribonucleoprotein particles of unknown function (Kickhoefer et al, 1999). A recent addition to the PARP family is PARP-3 that is localized to the centrosome and appears to modulate cell cycle progression (Augustin et al, 2003).…”

PARP-1 binds E2F-1 independently of its DNA binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during re-entry of quiescent cells into S phase

“…Products of the poly(ADP-ribose) polymerase (PARP) gene family, which now includes PARP-1, -2, -3, v-PARP, and tankyrase (Smith et al, 1998;Ame et al, 1999;Johansson, 1999;Kickhoefer et al, 1999), catalyse the poly(ADP-ribosyl)ation of various nuclear substrates utilizing NAD as a substrate. These various PARPs exhibit striking homology in their C-terminal catalytic domains, but differ significantly in their N-terminal domains and in their subcellular localizations.…”