mRNA surveillance in mammalian cells: The relationship between introns and translation termination

Abstract

In mammals, as in all organisms examined, mRNAs that prematurely terminate translation are abnormally reduced in abundance by a mechanism called nonsense-mediated mRNA decay (NMD) or mRNA surveillance (for reviews, see Maquat, 1995, 1996; Ruiz-Echevarria & Peltz, 1996; Li & Wilkinson, 1998; Culbertson, 1999; Hentze & Kulozik, 1999; Hilleren & Parker, 1999). This mechanism is thought to have evolved to eliminate nonsense-containing RNAs that arise as a consequence of (1) mutations in germ-line or somatic DNA or (2) routine abnormalities in gene expression due to abnormalities in, for example, transcription initiation, splicing, and somatic rearrangements of the type that characterize the immunoglobulin and T-cell receptor genes. The elimination of nonsense-containing mRNAs protects cells from the potentially deleterious effects of the encoded truncated proteins, which can manifest new or dominant-negative functions (Kazazian et al., 1992; Pulak & Anderson, 1993; Hall & Thein, 1994; Cali & Anderson, 1998). In addition to eliminating abnormal transcripts, NMD also regulates the expression of certain mRNAs that are not abnormal. Examples in mammalian cells are provided by certain selenoprotein mRNAs that terminate translation at a UGA codon for the inefficiently incorporated amino acid selenocysteine (Sec; Moriarty et al., 1997, 1998). Other examples will undoubtedly resemble natural substrates found in other organisms such as the alternatively spliced mRNAs of Caenorhabditis elegans that retain an internal exon harboring an in-frame termination codon (Morrison et al., 1997), and transcripts of Saccharomyces cerevisiae that contain a small open reading frame upstream of the primary open reading frame (Leeds et al., 1992; Pierrat et al., 1993).