Transcriptional elongation is the name given to the complex process by which nucleotides are added to the end of an RNA molecule as it is being constructed in the cell nucleus, replicating the blueprint for that molecule encoded in a DNA sequence. The RNA polymerase II complex is the protein machinery that accomplishes this work. In recent years researchers have identified age-related changes in the operation of this machinery that give rise to a greater incidence of errors and other changes in gene expression thought to detrimentally alter cell behavior.
Aging results in a major impairment of RNA and protein biosynthesis that contributes to aging-associated phenotypes. Research over the past two decades has mostly focused on quantitative changes of RNA and protein levels. However, recent work has shown that the quality of molecular processes involved in RNA and protein biosynthesis also declines with age, impacting not only the quantity but critically also the quality of the synthesized molecules. For example, errors during transcription and splicing can result in mRNAs carrying incorrect primary sequences, which can in turn lead to the production of toxic proteins that fuel aging-associated disease. Indeed, recent unbiased screens for factors causal to age-dependent retinal degeneration in flies or for new senescence regulators, identified transcriptional initiation and elongation factors as among the top hits.
It remains largely elusive how individual processes are affected during aging and what their specific contribution to age-related functional decline is. This review discusses a series of recent publications that has shown that transcription elongation is compromised during aging due to increasing DNA damage, stalling of RNA polymerase II, erroneous transcription initiation in gene bodies, and accelerated RNA polymerase II elongation. Importantly, several of these perturbations likely arise from changes in chromatin organization with age. Thus, taken together, this work establishes a network of interlinked processes contributing to age-related decline in the quantity and quality of RNA production.
Link: https://doi.org/10.1016/j.tcb.2024.11.005
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