Endogenous aldehyde-induced DNA-protein crosslinks (DPCs) are efficiently resolved by transcription-coupled repair (TCR), protecting against metabolic genotoxins. This process explains the molecular pathogenesis of diseases like AMeDS and Cockayne syndrome. Effective aldehyde clearance and TCR are crucial for maintaining genomic integrity in transcribed regions.
April 2024 – Nature Cell Biology
Key takeaways
- Efficient repair of DNA-protein crosslinks (DPCs) by transcription-coupled repair (TCR) is crucial for protecting against metabolic genotoxins: DPCs, which can obstruct DNA replication and transcription, are effectively removed by TCR, a process where RNA polymerase stalls at DNA lesions, triggering repair mechanisms. This is essential for preventing cellular damage and maintaining normal cellular functions
- Effective aldehyde clearance mechanisms are vital for maintaining genomic integrity, particularly in actively transcribed regions: Aldehydes, common metabolic byproducts, can form harmful DPCs if not cleared efficiently. Enzymes such as ADH5 and ALDH2 play key roles in detoxifying aldehydes, thus preventing the accumulation of DPCs. This clearance is especially important in regions of the genome that are frequently transcribed, as they are more susceptible to damage
- Deficiencies in DPC repair and aldehyde clearance processes are linked to premature ageing and related disorders such as AMeDS and Cockayne syndrome: Genetic deficiencies in the proteins responsible for DPC repair and aldehyde detoxification can lead to diseases characterised by premature ageing, such as AMeDS and Cockayne syndrome. These conditions manifest through symptoms like bone marrow failure, developmental defects, and neurodegeneration, highlighting the importance of these repair mechanisms
- Maintaining robust TCR and aldehyde detoxification systems can contribute to longevity and healthy ageing by preventing genomic damage: Ensuring the efficient functioning of TCR and aldehyde detoxification pathways helps preserve genomic integrity over time. By preventing the accumulation of DNA damage, these systems play a crucial role in promoting longevity and reducing the risk of age-related diseases, thereby supporting healthier ageing processes
Read the article at: Oka, Yasuyoshi, et al. “Endogenous Aldehyde-Induced DNA–Protein Crosslinks Are Resolved by Transcription-Coupled Repair.” Nature Cell Biology, vol. 26, May 2024, pp. 784-796, doi:10.1038/s41556-024-01401-2.