The placement of this protein outside of the defined clades likely reflects the large selleck bio changes found in C. elegans PARPs. The PARP lineages include one clade, Clade 1, which contains representatives from five of the six so called eukaryotic supergroups, Plantae, Opisthokonts, Chromalveolates, Excavates, and Amoebo zoa. There is no completely sequenced species available from the sixth supergroup, Rhizaria. This broad distribution suggests that the last common ancestor of all extant eukaryotes encoded a gene similar to those of Clade 1. Clade 6 is only found in three of the eukaryotic supergroups, however, the posi tion of this clade as sister group to all other members of the PARP superfamily and the placement of these groups within eukaryotes supports the hypothesis that the last common eukaryote also encoded such a gene.

Clade 1, the PARP1 clade Clade 1 is the most broadly distributed PARP clade among eukaryotes. The distribution of Clade1 proteins among eukaryotic species suggests that there was at least one Clade 1 like PARP protein encoded in the genome of their last common ancestor. This group of PARPs can be subdivided into nine subclades. Almost all members of Clade 1 are charac terized by the presence of WGR and PARP regulatory domains in addition to the PARP catalytic domains, one of the reasons we placed these proteins together. The WGR domain is found in PARPs as well an Escherichia coli molybdate metabolism regulator and other proteins of unknown function. Its exact function is unclear, but it is proposed to be a nucleic acid binding domain.

The PRD domain is found only in Clade 1 PARP proteins and has been shown to increase the poly ation activity of proteins that contain it. Consistent with the presence of PRD domains, many members of Clade 1 have been demonstrated to have poly ation activity, making it likely that most if not all members have this activity, this is also supported by the finding that the so called HYE catalytic triad is conserved in almost all of these proteins. Another commonality between members of Clade 1 is that many of them have been shown to have roles in DNA repair. Other common domains found in Clade 1 proteins are zinc finger DNA binding domains, BRCT domains and PADR1 domains. The BRCT domain, originally iden tified in the C terminus of the BRCA 1 protein, is usually found in proteins involved in cell cycle regulation and or DNA repair.

The PADR1 domain is found only in PARPs and is of unknown function. Clade 1A is found in Amoebozoa, Opisthokonta Carfilzomib and Chromalveolates and is the sister group to most of the other Clade 1 subclades. This subclade is unique within Clade 1 in containing proteins with ankyrin repeats, in addition to WGR, PRD and PARP catalytic domains. Clade 1B contains members from both the Opistho konta and the Excavata. This subclade is typified by human PARP1, the founding member of the superfamily.