Nucleases of the metallo-β-lactamase family and their role in DNA and RNA metabolism

Proteins of the metallo-beta-lactamase family with either demonstrated or predicted nuclease activity have been identified in a number of organisms ranging from bacteria to humans and has been shown to be important constituents of cellular metabolism. Nucleases of this family are believed to utilize a zinc-dependent mechanism in catalysis and function as 5' to 3' exonucleases and/or endonucleases in such processes as 3' end processing of RNA precursors, DNA repair, V(D)J recombination, and telomere maintenance. Examples of metallo-beta-lactamase nucleases include CPSF-73, a known component of the cleavage/polyadenylation machinery, which functions as the endonuclease in 3' end formation of both polyadenylated and histone mRNAs, and Artemis that opens DNA hairpins during V(D)J recombination. Mutations in two metallo-beta-lactamase nucleases have been implicated in human diseases: tRNase Z required for 3' processing of tRNA precursors has been linked to the familial form of prostate cancer, whereas inactivation of Artemis causes severe combined immunodeficiency (SCID). There is also a group of as yet uncharacterized proteins of this family in bacteria and archaea that based on sequence similarity to CPSF-73 are predicted to function as nucleases in RNA metabolism. This article reviews the cellular roles of nucleases of the metallo-beta-lactamase family and the recent advances in studying these proteins.