The fidelity of transcription in human cells

Abstract

To determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others. Cross-referencing the errors that we detected with various genetic and epigenetic features of the human genome revealed that the in vivo error rate in human cells changes along the length of a transcript and is further modified by genetic context, repetitive elements, epigenetic markers, and the speed of transcription. Our experiments further suggest that BRCA1, a DNA repair protein implicated in breast cancer, has a previously unknown role in the suppression of transcription errors. Finally, we analyzed the distribution of transcription errors in multiple tissues of a new mouse model and found that they occur preferentially in neurons, compared to other cell types. These observations lend additional weight to the idea that transcription errors play a key role in the progression of various neurological disorders, including Alzheimer’s disease.

Nurturing longevity through natural compounds: Where do we stand, and where do we go?

“…Conversely, sustained splicing regulation with age, including finely tuned alternative splicing mechanisms, is a part of the premises for the extraordinarily long life of naked mole rat (B. P. Lee et al, 2020). In addition, the loss of transcriptional fidelity during aging is linked to a faster but less accurate transcriptional elongation speed (RNA polymerase II speed), which is associated with a decrease in the number of unspliced transcripts and an increase in the formation of circular RNAs (Chung et al, 2023;Debès et al, 2023;Gyenis et al, 2023). Moreover, slowing down RNA polymerase II speed through wellknown lifespan-extending interventions such as dietary restriction and insulin/IGF signaling can reverse age-associated transcriptome shifts (Debès et al, 2023).…”

Selective manipulation of the host RNA-polymerase transcription fidelity increases phenotypic mutations in an insectParvovirus

“…The most studied source of phenotypic mutations is translational errors, using model reporter systems (1-3) such as programmed frameshifting or stop codon read-through, that give signals without need for mass spectrometry methods which are still limiting. Advances in RNA sequencing recently unveiled RNA mutation rates, which are higher than DNA mutation rates, as an important source of phenotypic mutations (1,(4)(5)(6). Yet the mechanism providing these mutations are not well understood and has mainly been studied in the context of artificial, error-prone transcription systems (1)(2)(3).…”

ZNF574 is a Quality Control Factor For Defective Ribosome Biogenesis Intermediates

“…For instance, environmental stresses like ultraviolet radiaLon [4][5][6][7] and reacLve oxygen species 8,9 can damage both the ribosomal RNA (rRNA) and ribosomal proteins. GeneLc perturbaLons 10,11 , errors during transcripLon 12,13 and translaLon 14,15 , as well as compromised post-transcripLonal modificaLons 16 can impair ribosome biogenesis, yielding non-funcLonal biogenesis intermediates. Faulty ribosome producLon leads to decreased protein synthesis, increased cellular stress, and ofen cell death 17 .…”