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. 2010 Oct;38(18):6186-94.
doi: 10.1093/nar/gkq449. Epub 2010 May 27.

Extensive frameshift at all AGG and CCC codons in the mitochondrial cytochrome c oxidase subunit 1 gene of Perkinsus marinus (Alveolata; Dinoflagellata)

Isao Masuda  1 , Motomichi Matsuzaki, Kiyoshi Kita
Affiliations

Extensive frameshift at all AGG and CCC codons in the mitochondrial cytochrome c oxidase subunit 1 gene of Perkinsus marinus (Alveolata; Dinoflagellata)

Isao Masuda et al. Nucleic Acids Res. 2010 Oct.

Abstract

Diverse mitochondrial (mt) genetic systems have evolved independently of the more uniform nuclear system and often employ modified genetic codes. The organization and genetic system of dinoflagellate mt genomes are particularly unusual and remain an evolutionary enigma. We determined the sequence of full-length cytochrome c oxidase subunit 1 (cox1) mRNA of the earliest diverging dinoflagellate Perkinsus and show that this gene resides in the mt genome. Apparently, this mRNA is not translated in a single reading frame with standard codon usage. Our examination of the nucleotide sequence and three-frame translation of the mRNA suggest that the reading frame must be shifted 10 times, at every AGG and CCC codon, to yield a consensus COX1 protein. We suggest two possible mechanisms for these translational frameshifts: a ribosomal frameshift in which stalled ribosomes skip the first bases of these codons or specialized tRNAs recognizing non-triplet codons, AGGY and CCCCU. Regardless of the mechanism, active and efficient machinery would be required to tolerate the frameshifts predicted in Perkinsus mitochondria. To our knowledge, this is the first evidence of translational frameshifts in protist mitochondria and, by far, is the most extensive case in mitochondria.

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Figures

Figure 1.
Figure 1.
Southern hybridization with Pmcox1 and a nuclear control probe. Southern hybridization using Pmcox1 (left) and nuclear LSU rDNA (right) probes. Lanes 1–4, P. marinus genomic DNA digested with AccI (1), BamHI (2), EcoRI (3) and HindIII (4); lane 5, uncut genomic DNA.
Figure 2.
Figure 2.
(A) Nucleotide sequence of Pmcox1 and its three frame translation. Gray boxes denote COX1-like amino acid sequences. Nucleotides in uppercase represent the sequence motifs found in transition areas of the reading frame where COX1-like amino acid sequences are deduced. AGG and CCC codons in the motifs are highlighted in red and blue, respectively. (B) Schematic model of Pmcox1 mRNA and the COX1-like blocks. COX1-like amino acid sequences distributed across three reading frames are represented by gray boxes labeled with Roman numerals. Numbers in parenthesis adjacent to the Roman numerals indicate the number of the amino acid residues. Red bars at the end of COX1-like blocks indicate UAGGY motifs containing in-frame AGG, and blue bars indicate CCCCUA motifs including in-frame CCC. Numbers above the open box indicate the positions of the first nucleotide in each motif. The uppermost bar indicates the probe region used for Southern hybridization with arrows indicating the primer locations.
Figure 3.
Figure 3.
Alignment of multiple COX1 amino acid sequences of P. marinus and related protists. The sequence for Perkinsus was predicted based on the frameshift model. Asterisks, colons and dots indicate identical residues, conserved and semi-conserved substitutions, respectively. Residues highlighted in black are conserved amino acid essential for cytochrome c oxidase function: His94 (ligand for heme a), His276 (ligand for CuB), Glu278 (D-channel), His 325, His326 (ligand for CuB), Lys354 (for K-channel), His411 (ligand for heme a3) and His413 [ligand for heme a; numbers are according to Paracoccus denitrificans homolog, (28)]. The red and blue arrowheads indicate the motifs (UAGGY and CCCCUA, respectively) where the reading frame is hypothetically shifted. Note that the glycine and proline residues at the frameshift sites are often highly conserved (highlighted in red and blue, respectively). The open boxes indicate tryptophans coded by UGA codons in Pmcox1 and those conserved at the homologous positions in related species. cox1 sequences were obtained from the NCBI database for Oxyrrhis marina (Omar, EF680822), Alexandrium catenella (Acat, AB374235), Plasmodium falciparum (Pfal, AY282930) and Thalassiosira pseudonana (Tpse, DQ186202). Note that the ciliate genes are not included because they are highly divergent and the gene length also differs greatly from those of related alveolates.
Figure 4.
Figure 4.
Possible mechanisms of frameshift-dependent translation at AGG and CCC codons of Perkinsus mt genes. (A) A ribosome stalled by tRNA limitation induces a ribosomal frameshift. When an in-frame AGG or CCC moves into the ribosome A site during translation, the ribosome stalls due to the limitation of the corresponding tRNA molecules, and the reading frame is subsequently shifted to the +1 frame. Translation then restarts in the new frame. In the case of CCCCUA, two consecutive frameshifts occur. (B) Specialized tRNAs recognize non-triplet codons, AGGY and CCCCU, and the reading frame shifts forward by one (AGGY) or two (CCCCU) bases.
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