ional phosphoglucose isomerase autocrine motility factor. This binding inhibits polyubiquitina tion of PGI AMF, stabilizing the protein. PARP1 in humans is regulated by ubiquitination and has been shown to bind to the E2 enzyme hUBC9. Proteasome mediated proteolysis of ubiquitinated tan kyrase has also been documented, selleck products this is promoted by the auto poly ation of tankyrase, which releases the protein into the cytoplasm. This is similar to the mechanism whereby tankyrase poly ates the telomeric protein TRF1, releasing it from the telomere, allowing its ubiquitination and degradation and the regulation of axin by tankyr ase. There are likely to be more connections found in the future between post translational ADP ribosylation and ubiquitination. Recently, a connection between poly ation and SUMOylation has also been demonstrated.

PARP1 itself is SUMOylated, and this takes place within its automodification domain and does not regulate poly ation activity. Rather, PARP1s transcriptional co activator activity is modified. PARP1 can also form higher order complexes and influence SUMOylation of other proteins. In response to both heat shock and DNA damage, human PARP1 associates with the SUMO E3 ligase PIASy and this requires a PAR binding motif in this protein. Upon DNA damage, PIASy associates with PAR on PARP1 and subsequently its target NEMO binds and is SUMOylated by PIASy, leading to NF kap paB activation. Clearly, the interplay between poly ation and other post translational modifi cations is just beginning to be explored.

Conclusions We present here a large scale phylogenetic analysis of the PARP gene family that extends previous examina tion of this family. Several main conclusions can be drawn from our study. First, the phylogenetic distribu tion of the PARP protein family is tremendously broad across the eukaryotes, consistent with the last common ancestor of modern eukaryotes containing at least two PARP encoding genes. Second, two types of PARP like proteins were present in the LCEA, one likely func tioned in DNA repair and genomic maintenance and resembled modern members of Clade 1. The second probably had mART activity. Third, increasing numbers and types of PARP like protein are likely to be found as more eukaryotic organisms have their genomes sequenced.

Methods Retrieval Carfilzomib of the PARP gene sequences The initial sequence set was selected from the Pfam database, using the sequences identified as members of the PARP family. The full sequences of the proteins were retrieved from selleck chem inhibitor UniProt, using the links provided by Pfam. Additional sequences were retrieved from other eukaryotic organisms at the DOE Joint Genome Institute, the Broad Insti tute, the J. Craig Venter Institute ToxoDB, and the Arabidopsis Information Resource using BLAST searches based on human or Arabidopsis thaliana PARP catalytic domain sequences as search queries. Specific phylogenetically interesting genomes were also individually searched by BLAST to confirm the absence of P