van de Grint Jacinta, Raseta Marko, Brandt Renata, van Loon Yvette, Demmers Joris, Dealy Shannon, Chang Jiang, Hoeijmakers Jan, Pothof Joris
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, Netherlands.
Princess Maxima Center for Pediatric Oncology, Oncode Institute, Heidelberglaan, Netherlands.
Front Mol Biosci. 2025 Sep 8;12:1659589. doi: 10.3389/fmolb.2025.1659589. eCollection 2025.
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 , , and 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.
不断积累的DNA损伤在衰老过程中起着关键作用，尤其是在有丝分裂后组织中，它会破坏转录并导致转录应激——一种以转录效率降低为特征的状态。由于DNA损伤在基因组中的随机分布，转录应激对长基因的影响尤为严重。目前尚缺乏对诱导转录应激并导致衰老所需的转录阻断损伤（TBL）总数的估计。在这里，我们通过将实验数据与一个仅基于基本生物学原理的数学模型相结合，估计了随着年龄增长积累的TBL数量。我们使用5-乙炔基尿苷（EU）掺入法，评估了来自5周、12周和26周龄小鼠的皮肤成纤维细胞和肝脏组织中的转录活性，这些小鼠模型存在DNA修复缺陷，在5至26周龄之间表现出广泛的早衰特征。然后，我们将实验数据与我们的模型进行比较，该模型捕捉到了转录下降的总体趋势，支持了衰老过程中积累的DNA损伤与转录减少之间的相关性。我们发现野生型小鼠每天大约积累62个TBL，而DNA修复缺陷型小鼠的负担明显更高，每天积累1600 - 5000个TBL。这些见解为转录应激提供了定量的理解，这对于阐明衰老过程至关重要。
