Transcription errors induce proteotoxic stress and shorten cellular lifespan

Vermulst, Marc; Denney, Ashley S.; Lang, Michael J.; Hung, Chao Wei; Moore, Stephanie; Mosely, Arthur M.; Thompson, W. J.; Madden, Victoria J.; Gauer, Jacob W.; Wolfe, Katie J.; Summers, Daniel W.; Schleit, Jennifer; Sutphin, George L.; Haroon, Suraiya; Holczbauer, Ágnes; Caine, Joanne M.; Jorgenson, James W.; Cyr, Douglas M.; Kaeberlein, Matt; Strathern, Jeffrey N.; Duncan, Mara C.; Erie, Dorothy A.

doi:10.1038/ncomms9065

Cited by 75 publications

(92 citation statements)

References 43 publications

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“…Intriguingly, the synthesized minimal living bacterial genome requires GreA, whereas RecA was found to be dispensable 32 . The consequences of RNA errors in epigenetic inheritance 33 and proteome toxicity 34 are being explored as a mechanism underlying evolution and disease. In the radiation resistant bacterium Deinococcus radiodurans , tolerance to DNA breaks mostly depends on a robust proteome for proper DNA repair and not on more efficient DNA repair 35 .…”

Section: Transcription Fidelity Impedes Dsb Repairmentioning

confidence: 99%

The transcription fidelity factor GreA impedes DNA break repair

Sivaramakrishnan

Sepúlveda

Halliday

et al. 2017

Nature

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Homologous recombination repairs DNA double-strand breaks and must function even on actively transcribed DNA. Because break repair prevents chromosome loss, the completion of repair is expected to outweigh the transcription of broken templates. Yet, the interplay between DNA break repair and transcription processivity is unclear. Here we show that the transcription factor GreA inhibits break repair in Escherichia coli. GreA restarts backtracked RNA polymerase (RNAP) and hence promotes transcription fidelity. We report that removal of GreA results in dramatically enhanced break repair via the classical RecBCD-RecA pathway. Using a deep-sequencing method to measure chromosomal exonucleolytic degradation (XO-Seq), we demonstrate that the absence of GreA limits RecBCD-mediated resection. Our findings suggest that increased RNAP backtracking promotes break repair by instigating RecA loading by RecBCD, without the influence of canonical Chi signals. The idea that backtracked RNAP can stimulate recombination presents a DNA transaction conundrum: a transcription fidelity factor compromises genomic integrity.

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Section: Transcription Fidelity Impedes Dsb Repairmentioning

confidence: 99%

The transcription fidelity factor GreA impedes DNA break repair

Sivaramakrishnan

Sepúlveda

Halliday

et al. 2017

Nature

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“…This includes conversion of oxidative damage, for example, 8-OHdG [28] and has been established for various RNA polymerases, including the mitochondrial RNA polymerase [29••]. ‘Transcriptional mutagenesis’ has been recently implicated in cellular stress and premature cellular aging [30••]. …”

Section: Hypothesis: Mtdna Damage Contributes To the Mutator Phenotypmentioning

confidence: 99%

Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1α, p53, and DNA damage. A hypothesis

Safdar

Annis

Kraytsberg

et al. 2016

Current Opinion in Genetics & Development

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The mtDNA mutator mouse lacks the proofreading capacity of the sole mtDNA polymerase, leading to accumulation of somatic mtDNA mutations, and a profound premature aging phenotype including elevated oxidative stress and apoptosis, and reduced mitochondrial function. We have previously reported that endurance exercise alleviates the aging phenotype in the mutator mice, reduces oxidative stress, and enhances mitochondrial biogenesis. Here we summarize our findings, with the emphasis on the central role of p53 in these adaptations. We demonstrate that mtDNA in sedentary and exercised PolG mice carry similar amounts of mutations in muscle, but in addition to that sedentary mice have more non-mutational damage, which is mitigated by exercise. It follows therefore that the profound alleviation of the mtDNA mutator phenotype in muscle by exercise may not require a reduction in mtDNA mutational load, but rather a decrease of mtDNA damage and/or oxidative stress. We further hypothesize that the observed ‘alleviation without a reduction of mutational load’ implies that the oxidative stress in PolG muscle is maintained, at least in part, by the ‘malicious cycle’, a hypothetical positive feedback potentially driven by the ‘transcriptional mutagenesis’, that is the conversion of chemically modified nucleotides into mutant RNA bases by the mitochondrial RNA polymerase.

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“…Increased Pol-II elongation speed can lead to elevated transcriptional errors, because the proofreading capacity of Pol-II is reduced (8). To explore the potential impact of transcriptional elongation on transcript quality beyond splicing, we measured the number of mismatches in aligned reads for each gene normalized by its respective expression level.…”

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confidence: 99%

Aging-associated changes in transcriptional elongation influence metazoan longevity

Debès

Grönke

Karalay

et al. 2019

Preprint

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Aging impairs cellular homeostasis, thereby compromising multiple cellular processes, including transcription and splicing. However, the molecular mechanisms at work, and hence ways of preventing loss of transcriptional fidelity, are so far elusive. We analyzed changes in genome-wide, transcription-coupled processes with age in Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Rattus norvegicus and Homo sapiens. Using total RNA profiling, we quantified transcriptional elongation speed (Pol-II speed). Genomeaveraged Pol-II speed increased with age in all five species. Lifespan-extending dietary restriction and lowered insulin signaling both rescued these age-related trends.Experimentally reducing Pol-II speed in worms and flies increased lifespan. These findings uncover fundamental molecular mechanisms driving animal aging and underlying lifespanextending interventions, and point to possible preventative measures. One-sentence summaryGenome-wide analysis of total RNA during aging reveals increased transcriptional elongation speed and decreased splicing efficiency, with an impact on longevity. Main TextAging impairs a wide range of cellular processes, many of which affect the quality and concentration of proteins. Among these, transcription is particularly important, because it is the main regulator of protein levels (1-3). Transcriptional elongation is critical for proper mRNA synthesis, due to its association with pre-mRNA processing steps such as splicing, editing, and 3' end formation (4, 5). Indeed, dysregulation of transcriptional elongation can lead to a number of diseases (6). During aging, animal transcriptomes undergo extensive remodeling, with large-scale changes in expression of transcripts involved in signaling pathways, DNA damage response, protein homeostasis (e.g. the ubiquitin-proteasome pathway), immune response, and stem cell plasticity (7). Further, some studies detected an age-related increase in variability and error of gene expression (8-10). This prior work has provided insights into how the transcriptome adapts to, and is affected by, aging-associated cellular stress. However, it is not known if, or to what extent, the transcription process itself is affected by aging. In this study, we have investigated how the kinetics of transcription is affected by aging, how such changes can affect mRNA biosynthesis, and the role of these changes in age-related loss of function in the whole organism.The translocation speed of RNA polymerase II (Pol-II) during transcription can be monitored using total RNA sequencing (RNA-seq), because the distribution of reads in introns is affected by the elongation speed of Pol-II. Co-transcriptional splicing results in a characteristic saw-tooth pattern of the read coverage, observable from total RNA-seq or nascent RNA-seq measurements (11,12). The read coverage generally decreases 5' to 3' along an intron and the extent of this decrease depends on Pol-II speed: the faster the elongation, the shallower the slope (13-15), i.e. fast elongation of Pol-II r...

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Transcription errors induce proteotoxic stress and shorten cellular lifespan

Cited by 75 publications

References 43 publications

The transcription fidelity factor GreA impedes DNA break repair

The transcription fidelity factor GreA impedes DNA break repair

Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1α, p53, and DNA damage. A hypothesis

Aging-associated changes in transcriptional elongation influence metazoan longevity

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