Critical Review CNBP: A Multifunctional Nucleic Acid Chaperone Involved in Cell Death and Proliferation Control Nora B. Calcaterra, Pablo Armas, Andrea M. J. Weiner, and Mariana Borgognone Instituto de Biologı´a Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Cientı´ficas y Te´cnicas (CONICET) - A ´ rea Biologı´a General, Dpto. de Ciencias Biolo´gicas, Facultad de Ciencias Bioquı´micas y Farmace´uticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK-Rosario, Argentina Summary Cellular nucleic acid binding protein (CNBP) has been impli- cated in vertebrate craniofacial development and in myotonic dystrophy type 2 (DM2) and sporadic inclusion body myositis (sIBM) human diseases. In these seemingly unrelated biological processes, CNBP appears to be involved in controlling cell death and proliferation rates. Low levels of CNBP may reduce rate of global protein synthesis, thereby reducing proliferation and increasing apoptosis. Conversely, CNBP might affect tran- scription of genes required for cell proliferation. Experimental evidences gathered so far make it difficult to ascertain or rule out any of these possibilities. Moreover, both possibilities may not be mutually exclusive. CNBP is a small and strikingly con- served single-stranded nucleic acid binding protein that is able to bind DNA as well as RNA. CNBP has a broad spectrum of targets, ranging from regulatory sites in gene promoters to translational regulatory elements in mRNA untranslated regions. Biochemical experiments have recently shed light on the possible mechanism of action for CNBP, which may act as a nucleic acid chaperone catalyzing the rearrangement of G-rich nucleic acid secondary structures likely relevant for transcrip- tional and/or translational gene regulation. This review focuses on the involvement of CNBP in vertebrate craniofacial develop- ment and human DM2 and sIBM diseases, as well as on the bio- chemical and structural features of CNBP and its cellular and molecular mechanism of action. Ó 2010 IUBMB IUBMB Life, 62(10): 707–714, 2010 Keywords cell death; chaperones; protein function; structural biol- olgy; transcription factors; transcriptional regulation; col- lagen gene expression. Abbreviations ZNF9, zinc-finger protein 9; CNBP, cellular nucleic acid binding protein; CCHC, Cys-Cys-His-Cys; NC, neural crest; DM2, myotonic dystrophy type 2; OMIM, online Mendelian inheritance in man; UTR, untranslated region; TOP, terminal oligopyrimidine tract; PABP1, Poly(A)-binding protein 1; eEF1A, eu- karyotic elongation factor 1A; eEF2, eukaryotic elon- gation factor 2; IRES, internal ribosomal entry site; PEST, Pro, Glu, Ser or Thr-enriched region; PKA, cAMP-dependent protein kinase; ECR, evolutionarily conserved regions; ssDNA, single-stranded DNA; G4, G-quadruplexes; hpf, hours-post fertilization; sIBM, sporadic inclusion body myositis; APP, amyloid pre- cursor protein; Ab, b-amyloid. INTRODUCTION The gene coding for cellular nucleic acid binding protein has for years been called ZNF9. Currently, the Human Genome Organization Gene Nomenclature Committee has adopted ‘‘CNBP’’ as an acronym and ‘‘CCHC-type zinc finger, nucleic acid binding protein’’ as the full name for this gene. The Uni- versal Protein Resource recommends ‘‘cellular nucleic acid binding protein’’ and ‘‘CNBP’’ as the full name and acro- nym for the protein, respectively. Therefore, throughout this review, we have used the nomenclature recommended by these committees. Various reports have implicated CNBP in two apparently unrelated biological processes: the human disease myotonic dys- trophy type 2 (DM2, proximal myotonic myopathy, OMIM # 602668) ( 1) and embryogenesis of craniofacial structures (2–4). From these findings, extensive information on the CNBP expression pattern and its possible roles in these processes, as well as on protein structural and biochemical characteristics, has been published. However, although both lines of research have progressed significantly, a complete understanding of Received 1 July 2010; accepted 11 August 2010 Address correspondence to: Nora B. Calcaterra, IBR-CONICET, Suipacha 531, S2002LRK-Rosario, Argentina. E-mail: calcaterra@ibr.gov.ar ISSN 1521-6543 print/ISSN 1521-6551 online DOI: 10.1002/iub.379 IUBMB Life, 62(10): 707–714, October 2010