The multifunctional SNM1 gene family: not just nucleases

Abstract

The archetypical member of the SNM1 gene family was discovered 30 years ago in the budding yeast Saccharomyces cerevisiae. This small but ubiquitous gene family is characterized by metallo-beta-lactamase and beta-CASP domains, which together have been demonstrated to comprise a nuclease activity. Three mammalian members of this family, SNM1A, SNM1B/Apollo and Artemis, have been demonstrated to play surprisingly divergent roles in cellular metabolism. These pathways include variable (diversity) joining recombination, nonhomologous end-joining of double-strand breaks, DNA damage and mitotic cell cycle checkpoints, telomere maintenance and protein ubiquitination. Not all of these functions are consistent with a model in which these proteins act only as nucleases, and indicate that the SNM1 gene family encodes multifunctional products that can act in diverse biochemical pathways. In this article we discuss the various functions of SNM1A, SNM1B/Apollo and Artemis.

Figure 1. Structural domains of mammalian SNM1 proteins and identified interacting partners

Domains are described in the text. Horizontal lines indicate identified regions of interaction with the proteins. β-CASP: β-CPSF–Artemis–SNM1–PSO2; DNA-PKcs: DNA-dependent protein kinase catalytic subunit; MBL: Metallo-β-lactamase; MRN: MRE11-RAD50-NBS1; PBZ: Poly(ADP-ribose)-binding zinc finger; SCD: (Serine/threonine)–glutamine cluster domain; SNM1: Sensitivity to nitrogen mustard.

Figure 2. Sites of Artemis phosphorylation that have been confirmed in vivo

S516, S534, S538 and S645 are all serine–glutamine sites and have been confirmed to be phosphorylated in vivo through the use of phospho-specific antibodies [86,93]. The S385 and S518 sites have been confirmed by mass spectroscopy and phospho-specific antibodies [39]. The S385 site represents a consensus sequence for phosphorylation by casein kinase II. The S518 site is a serine–proline motif. β-CASP: β-CPSF–Artemis–SNM1–PSO2; MBL: Metallo-β-lactamase; SCD: (Serine/threonine)–glutamine cluster domain.

Figure 3. Model for the functions of Artemis in mammalian cells

In response to double-strand breaks created by IR or the RAG1/RAG2 complex, Artemis interacts with autophosphorylated DNA-PKcs to facilitate repair. These processes are independent of Artemis phosphorylation and require only the SNM1 domain (left side of schematic). In response to various forms of cellular stress, Artemis is phosphorylated at multiple sites and acts in various response pathways (right side of schematic). DNA-PKcs: DNA-dependent protein kinase catalytic subunit; IR: Ionizing radiation; NHEJ: Nonhomologous end joining; P-Artemis: Phosphorylated Artemis; SNM1: Sensitivity to nitrogen mustard; V(D)J: Variable (diversity) joining.