Transcription stress Counteracted by Nutritional interventions of Exceptional importance for rare DNA Repair disorders

• Applicant: Professor Jan Hoeijmakers, Ph.D.
• Subject Area: Biogerontology and Geriatric Medicine ; General Genetics and Functional Genome Biology ; Pediatric and Adolescent Medicine
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460905236

Rare genome instability syndromes such as Cockayne syndrome (CS) and trichothiodystrophy (TTD) are caused by defects in transcription-coupled DNA repair (TCR) - with or without additional global genome nucleotide excision repair (GG-NER) deficiency. Phenotypically, these disorders are characterized by segmental, but dramatic accelerated aging that reflects multi-morbidity in numerous organs and tissues. The most critical clinical hallmark is neurodegeneration, often limiting life expectancy to childhood and strongly affecting quality of life. Regrettably, presently no cure exists. In the past we have made major contributions to the current understanding of these repair systems: we cloned ~half of all relevant repair genes, resolved the molecular basis of many of the TCR and GG-NER syndromes, generated the vast majority of the mouse mutants, disclosed the strong connection with aging, and identified DNA damage induced decreasing transcriptional output (transcription stress) as a novel feature of accelerated and normal aging. Recently, we have made the counterintuitive discovery that merely reducing daily nutritional intake is of tremendous benefit for DNA repair-deficient, severely growth-retarded progeroid mouse mutants, which very closely mimic the human repair disorders. All features of accelerated aging were unequivocally strongly delayed, and lifespan extended by 200%(!), simply by reducing food intake by 30%. Most impressive was the effect on neurodegeneration: instead of slowing down or halting signs of severe neurodegeneration, tremors and imbalance even completely disappeared, revealing multiple overall significant improvements. Translation of these remarkable observations to a first TTD (XPD) patient has recently even surpassed the mouse findings: when parents chose to partially reduce caloric intake in their child (at the age of 7) the progressive neurological decline not only stopped, but motor and cognition even strongly improved, her very severe tremors disappeared, she started for the first time walking, talking, counting and enjoys now over 2 years very stable health, which has already led on the basis of our findings to reversing the guidelines for nutritional care of CS/TTD children: instead of more, CS/TTD patients should get less food.Within this consortium we aim to mechanistically understand the intriguing interplay between nutrition, metabolism, transcription stress and neuronal functioning, further improve nutritional guidelines and explore effects of nutritional interventions in other rare genome instability syndromes (e.g. Fanconi anemia), that may benefit as well, based on our finding that dietary restriction reduces endogenous DNA damage load and thereby transcriptional stress. These aspects will be studied at multiple levels (e.g. cells, organoids, mouse models, and patients) to provide improved evidence-based advice and further optimise nutritional and medical strategies for these rare devastating diseases.

• DFG Programme: Research Grants
• International Connection: France, Italy, Netherlands, Turkey
• Cooperation Partners: Professor Umut Altunoglu, Ph.D.; Professor Vincent Laugel, Ph.D.; Pier G. Mastroberardino, Ph.D.; Wilbert Vermeij, Ph.D.