TY  - JOUR
A1  - Saffert, Paul
A1  - Adamla, Frauke
A1  - Schieweck, Rico
A1  - Atkins, John F.
A1  - Ignatova, Zoya
T1  - An Expanded CAG Repeat in Huntingtin Causes+1 Frameshifting
JF  - The journal of biological chemistry
N2  - Maintenance of triplet decoding is crucial for the expression of functional protein because deviations either into the -1 or +1 reading frames are often non-functional. We report here that expression of huntingtin (Htt) exon 1 with expanded CAG repeats, implicated in Huntington pathology, undergoes a sporadic +1 frameshift to generate from the CAG repeat a trans-frame AGC repeat-encoded product. This +1 recoding is exclusively detected in pathological Htt variants, i.e. those with expanded repeats with more than 35 consecutive CAG codons. An atypical +1 shift site, UUC C at the 5 end of CAG repeats, which has some resemblance to the influenza A virus shift site, triggers the +1 frameshifting and is enhanced by the increased propensity of the expanded CAG repeats to form a stem-loop structure. The +1 trans-frame-encoded product can directly influence the aggregation of the parental Htt exon 1.
KW  - aggregation
KW  - Huntington disease
KW  - translation
KW  - translation regulation
KW  - trinucleotide repeat disease
KW  - frameshifting
KW  - seeding
Y1  - 2016
U6  - https://doi.org/10.1074/jbc.M116.744326
SN  - 0021-9258
SN  - 1083-351X
VL  - 291
SP  - 18505
EP  - 18513
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - GEN
A1  - Bentele, Kajetan
A1  - Saffert, Paul
A1  - Rauscher, Robert
A1  - Ignatova, Zoya
A1  - Bluethgen, Nils
T1  - Efficient translation initiation dictates codon usage at gene start
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - The genetic code is degenerate; thus, protein evolution does not uniquely determine the coding sequence. One of the puzzles in evolutionary genetics is therefore to uncover evolutionary driving forces that result in specific codon choice. In many bacteria, the first 5-10 codons of protein-coding genes are often codons that are less frequently used in the rest of the genome, an effect that has been argued to arise from selection for slowed early elongation to reduce ribosome traffic jams. However, genome analysis across many species has demonstrated that the region shows reduced mRNA folding consistent with pressure for efficient translation initiation. This raises the possibility that unusual codon usage is a side effect of selection for reduced mRNA structure. Here we discriminate between these two competing hypotheses, and show that in bacteria selection favours codons that reduce mRNA folding around the translation start, regardless of whether these codons are frequent or rare. Experiments confirm that primarily mRNA structure, and not codon usage, at the beginning of genes determines the translation rate.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 912 
KW  - codon usage
KW  - mRNA structure
KW  - translation
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-441337
SN  - 1866-8372
IS  - 912
ER  - 
TY  - JOUR
A1  - Bentele, Kajetan
A1  - Saffert, Paul
A1  - Rauscher, Robert
A1  - Ignatova, Zoya
A1  - Bluethgen, Nils
T1  - Efficient translation initiation dictates codon usage at gene start
JF  - Molecular systems biology
N2  - The genetic code is degenerate; thus, protein evolution does not uniquely determine the coding sequence. One of the puzzles in evolutionary genetics is therefore to uncover evolutionary driving forces that result in specific codon choice. In many bacteria, the first 5-10 codons of protein-coding genes are often codons that are less frequently used in the rest of the genome, an effect that has been argued to arise from selection for slowed early elongation to reduce ribosome traffic jams. However, genome analysis across many species has demonstrated that the region shows reduced mRNA folding consistent with pressure for efficient translation initiation. This raises the possibility that unusual codon usage is a side effect of selection for reduced mRNA structure. Here we discriminate between these two competing hypotheses, and show that in bacteria selection favours codons that reduce mRNA folding around the translation start, regardless of whether these codons are frequent or rare. Experiments confirm that primarily mRNA structure, and not codon usage, at the beginning of genes determines the translation rate.
KW  - codon usage
KW  - mRNA structure
KW  - translation
Y1  - 2013
U6  - https://doi.org/10.1038/msb.2013.32
SN  - 1744-4292
VL  - 9
IS  - 6
PB  - Nature Publ. Group
CY  - New York
ER  -