AUTHOR=van de Grint Jacinta , Raseta Marko , Brandt Renata , van Loon Yvette , Demmers Joris , Dealy Shannon , Chang Jiang , Hoeijmakers Jan , Pothof Joris 

TITLE=Transcriptional stress in aging: integrating experimental data and modeling to quantify DNA damage accumulation

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 12 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1659589

DOI=10.3389/fmolb.2025.1659589

ISSN=2296-889X

ABSTRACT=Accumulating DNA damage plays a crucial role in aging, particularly in post-mitotic tissues by disrupting transcription and causing transcriptional stress—a state marked by reduced transcriptional productivity. Transcriptional stress disproportionately affects long genes, due to the random distribution of DNA lesions across the genome. An estimate for the total number of transcription-blocking lesions (TBLs) required to induce transcriptional stress and contribute to aging is lacking. Here, we estimated the number of TBLs accumulating with age, by integrating experimental data with a mathematical model based solely on fundamental biological principles. Using 5-ethynyluridine (EU) incorporation, we assessed transcriptional activity in dermal fibroblasts and liver tissue from Ercc1−/−, Ercc1d/-, and Xpg−/− mice—models with DNA repair deficiencies that exhibit a wide range of premature aging features between 5 and 26 weeks of age. We then compared the experimental data to our model, which captured the overall trend of transcriptional decline, supporting a correlation between accumulating DNA damage and reduced transcription during aging. Wildtype mice were found to accumulate approximately 62 TBLs per day, whereas DNA repair-deficient mice exhibited a markedly higher burden, accumulating 1,600–5,000 TBLs daily. These insights offer a quantitative understanding of transcriptional stress, which is crucial for elucidating the aging process.