Slowly Repaired Bulky DNA Damages Modulate Cellular Redox Environment Leading to Premature Senescence
Yujie Zhang1, Peiyan Guo1, Wanchen Xiang1
1College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
Abstract:
Treatments on neoplastic diseases and cancer using genotoxic drugs often cause long-term health problems related to premature aging. The underlying mechanism is poorly understood. Based on the study of a long-lasting senescence-like growth arrest (10-12 weeks) of human dermal fibroblasts induced by psoralen plus UVA (PUVA) treatment, we here revealed that slowly repaired bulky DNA damages can serve as a "molecular scar" leading to reduced cell proliferation through persistent endogenous production of reactive oxygen species (ROS) that caused accelerated telomere erosion. The elevated levels of ROS were the results of mitochondrial dysfunction and the activation of NADPH oxidase (NOX). A combined inhibition of DNA-PK and PARP1 could suppress the level of ROS. Together with a reduced expression level of BRCA1 as well as the upregulation of PP2A and 53BP1, these data suggest that the NHEJ repair of DNA double-strand breaks may be the initial trigger of metabolic changes leading to ROS production. Further study showed that stimulation of the pentose phosphate pathway played an important role for NOX activation, and ROS could be efficiently suppressed by modulating the NADP/NADPH ratio. Interestingly, feeding cells with ribose-5-phosphate, a precursor for nucleotide biosynthesis that produced through the PPP, could evidently suppress the ROS level and prevent the cell enlargement related to mitochondrial biogenesis. Taken together, these results revealed an important signaling pathway between DNA damage repair and the cell metabolism, which contributed to the premature aging effects of PUVA, and may be generally applicable for a large category of chemotherapeutic reagents including many cancer drugs.
Insights
Genotoxic cancer drugs can cause premature aging via DNA damage, leading to persistent reactive oxygen species (ROS) production and telomere erosion. Inhibiting DNA repair pathways and modulating cellular metabolism can suppress ROS and mitigate aging effects.
Area of Science:
- Molecular Biology
- Cellular Metabolism
- Aging Research
Background:
- Genotoxic cancer treatments can induce premature aging.
- The mechanisms linking DNA damage to aging are not fully understood.
- Psoralen plus UVA (PUVA) treatment causes senescence-like growth arrest in fibroblasts.
Purpose of the Study:
- To elucidate the mechanism by which DNA damage from genotoxic drugs leads to premature aging.
- To identify key molecular players and pathways involved in this process.
- To explore potential therapeutic targets for mitigating drug-induced aging.
Main Methods:
- Induction of senescence-like growth arrest in human dermal fibroblasts using PUVA.
- Analysis of DNA damage repair pathways, including Non-Homologous End Joining (NHEJ).
- Measurement of reactive oxygen species (ROS) production, mitochondrial function, and NADPH oxidase (NOX) activity.
- Investigation of the pentose phosphate pathway (PPP) and NADP/NADPH ratio.
- Assessment of telomere length and cell morphology.
Main Results:
- Slowly repaired bulky DNA damage acts as a "molecular scar," causing persistent ROS production.
- ROS accelerates telomere erosion, contributing to premature aging.
- Mitochondrial dysfunction and NOX activation are key sources of elevated ROS.
- Inhibition of DNA-PK and PARP1, alongside altered BRCA1, PP2A, and 53BP1 expression, suggests NHEJ's role in initiating metabolic changes.
- Pentose phosphate pathway stimulation is crucial for NOX activation; modulating NADP/NADPH ratio and ribose-5-phosphate supplementation suppress ROS.
- Ribose-5-phosphate prevents cell enlargement linked to mitochondrial biogenesis.
Conclusions:
- A signaling pathway connects DNA damage repair to cellular metabolism, driving premature aging effects.
- This pathway is implicated in the aging effects of PUVA treatment.
- Findings may be applicable to various chemotherapeutic agents, including cancer drugs.
- Targeting this pathway could offer strategies to reduce chemotherapy-induced aging.
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