The eukaryotic Pso2/Snm1/Artemis proteins and their function as genomic and cellular caretakers

Abstract

DNA double-strand breaks (DSBs) represent a major threat to the genomic stability of eukaryotic cells. DNA repair mechanisms such as non-homologous end joining (NHEJ) are responsible for the maintenance of eukaryotic genomes. Dysfunction of one or more of the many protein complexes that function in NHEJ can lead to sensitivity to DNA damaging agents, apoptosis, genomic instability, and severe combined immunodeficiency. One protein, Pso2p, was shown to participate in the repair of DSBs induced by DNA inter-strand cross-linking (ICL) agents such as cisplatin, nitrogen mustard or photo-activated bi-functional psoralens. The molecular function of Pso2p in DNA repair is unknown, but yeast and mammalian cell line mutants for PSO2 show the same cellular responses as strains with defects in NHEJ, e.g., sensitivity to ICLs and apoptosis. The Pso2p human homologue Artemis participates in V(D)J recombination. Mutations in Artemis induce a variety of immunological deficiencies, a predisposition to lymphomas, and an increase in chromosomal aberrations. In order to better understand the role of Pso2p in the repair of DSBs generated as repair intermediates of ICLs, an in silico approach was used to characterize the catalytic domain of Pso2p, which led to identification of novel Pso2p homologues in other organisms. Moreover, we found the catalytic core of Pso2p fused to different domains. In plants, a specific ATP-dependent DNA ligase I contains the catalytic core of Pso2p, constituting a new DNA ligase family, which was named LIG6. The possible functions of Pso2p/Artemis/Lig6p in NHEJ and V(D)J recombination and in other cellular metabolic reactions are discussed. Correspondence

Mammalian SNM1 is required for genome stability

“…The yeast enzyme, which contains the conserved β-lactamase motif, is known to have a 5'-exonuclease activity which is required for its function in ICL repair [1,10]. The hSNM1 protein is also a 5'-exonuclease [11] and the SNM1 protein belongs to the β-CASP motif-containing family, which includes proteins that function in DNA repair, V(D)J recombination and RNA processing [12,13]. Hydrophobic cluster analysis of amino acid sequences reveals additional members of this family [12].…”

“…The hSNM1 protein is also a 5'-exonuclease [11] and the SNM1 protein belongs to the β-CASP motif-containing family, which includes proteins that function in DNA repair, V(D)J recombination and RNA processing [12,13]. Hydrophobic cluster analysis of amino acid sequences reveals additional members of this family [12]. Overproduction of SNM1 protein appears harmful to cells since over-expression is not stable [11,14], suggesting the exonuclease activity may need to be tightly regulated in its DNA processing activity.…”

A prototypical Fanconi anemia pathway in lower eukaryotes?

“…18 Hairpin opening activity may suggest a novel role for Pso2 outside ICL repair, although the relevant physiological processes that generate DNA hairpin substrates for Pso2 remain to be elucidated. 4,18,20 There are three Pso2 orthologs in vertebrates, SNM1A, SNM1B/Apollo and SNM1C/Artemis. 21 Like Pso2, SNM1A and SNM1B display 5' to 3' exonuclease activity, whereas SNM1C possesses endonuclease activity, cleaving 5' and 3' overhangs and hairpins.…”

Artemis interacts with the Cul4A-DDB1DDB2ubiquitin E3 ligase and regulates degradation of the CDK inhibitor p27

“…[1][2][3][4][5] Members of this family share the SNM1 conserved domain, characterized by a metallo-β-lactamase fold and an appended β-CASP (CPSF-Artemis-Snm1-Pso2) motif, the latter of which is unique to this family. 6,7 The SNM1 domain encompasses a nuclease activity in the SNM1/PSO2 proteins, which accounts for their function in DNA metabolism, such as that of SNM1B/Apollo in telomere resection 8,9 and that of Artemis in V(D)J recombination and the repair of DSBs by nonhomologous end-joining (NHEJ).…”