Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon

BMC Genetics
Yousuf A KhanManolis Kellis

Abstract

POLG, located on nuclear chromosome 15, encodes the DNA polymerase γ(Pol γ). Pol γ is responsible for the replication and repair of mitochondrial DNA (mtDNA). Pol γ is the only DNA polymerase found in mitochondria for most animal cells. Mutations in POLG are the most common single-gene cause of diseases of mitochondria and have been mapped over the coding region of the POLG ORF. Using PhyloCSF to survey alternative reading frames, we found a conserved coding signature in an alternative frame in exons 2 and 3 of POLG, herein referred to as ORF-Y that arose de novo in placental mammals. Using the synplot2 program, synonymous site conservation was found among mammals in the region of the POLG ORF that is overlapped by ORF-Y. Ribosome profiling data revealed that ORF-Y is translated and that initiation likely occurs at a CUG codon. Inspection of an alignment of mammalian sequences containing ORF-Y revealed that the CUG codon has a strong initiation context and that a well-conserved predicted RNA stem-loop begins 14 nucleotides downstream. Such features are associated with enhanced initiation at near-cognate non-AUG codons. Reanalysis of the Kim et al. (2014) draft human proteome dataset yielded two unique peptides that map unambigu...Continue Reading

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Citations

Sep 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Gary LoughranDmitry E Andreev
Dec 4, 2020·Nucleic Acids Research·Adam FrankishPaul Flicek
May 6, 2021·Nucleic Acids Research·Stephen J KiniryPavel V Baranov
May 13, 2021·Nature Communications·Irwin JungreisManolis Kellis
Oct 7, 2021·Nature Reviews. Genetics·Bradley W WrightPaul R Jaschke
Oct 12, 2021·Critical Reviews in Biochemistry and Molecular Biology·Yousuf A KhanAxel T Brunger

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Methods Mentioned

BETA
ribo-seq
deamidation

Software Mentioned

UCSC Genome Browser
Eukaryotic Linear Motif ( ELM )
Ensembl
MUSCLE
Clinvar
Visualization Applet for RNA secondary structure software ( VARNA
CodAlignView
Viz
tblastn
PeptideAtlas

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