Jan Hoeijmakers Group

DNA repair

Our Focus

This summary focusses on the contributions of Jan Hoeijmakers to the field of DNA repair and its consequences for cancer and aging: the main healthcare problems in developed societies. The team of Jan Hoeijmakers succeeded in cloning the first human DNA repair gene, Ercc1, followed by many more, discovered the very strong evolutionary conservation of DNA repair and an unexpected link with basal transcription. This allowed elucidation of the nucleotide excision repair (NER) reaction mechanism and the molecular basis of the cancer-prone disorder xeroderma pigmentosum (XP) and the -till then enigmatic- neurodevelopmental human repair syndromes, such as Cockayne syndrome and trichothiodystrophy. Subsequently, his team embarked upon the systematic generation of a series of mouse repair mutants, to cover the range from molecule to patient. These mouse mutants turned out to be extremely informative: they not only mimicked the corresponding human syndromes to an exceptional degree but also enabled detailed insight into the complex etiology of human repair diseases. In this way, he disclosed the balance between cancer and aging and the link of both with DNA damage.

His team identified which repair processes primarily protect from cancer and which from accelerated aging and succeeded in getting grip on the aging process in mice by modulating DNA repair and surprisingly by nutritional interventions. The acceleration of specific aging features was found to strictly correlate with the severity of defects in specific repair pathways. The spectrum of accelerated aging symptoms (which organs age fast) is determined by the type of repair defect (which pathway is affected). E.g. transcription-coupled repair primarily protects post-mitotic tissues such as the neuronal system from accelerated aging, cross-link repair the proliferative organs e.g. bone marrow. Conditional repair mice allow targeting cancer and/or accelerated aging to any organ, tissue or stage of development, for instance mice in which only the cerebellum or heart exhibit dramatic accelerated aging. The Ercc1Δ/- mutant, affected in at least 3 repair pathways, exhibits the most wide-spread premature aging phenotypes documented to date for any mammal: progressive neurodegeneration (dementia, ataxia, loss of hearing, vision, neuronal plasticity, etc.), osteoporosis, cardiovascular, hematological and immunological aging, thymic involution, cachexia, sarcopenia, early infertility, liver, kidney aging etc., accompanied by progressive behavioral-physiological-hormonal alterations, loss of stem cells, increased cellular senescence and gene expression patterns alike natural aging. Importantly, this mutant is found to be a superior model for Alzheimer and Parkinson disease addressing a tremendous unmet medical need. E.g. he recently discovered a connection between DNA damage and protein homeostatic stress explaining protein aggregates. These findings are fully consistent with the notion that aging is the most important risk factor for all these dementia’s.

Rapid accumulation of unrepaired DNA damage in these mice may cause cancer or premature cell death and senescence, but triggers also an anti-aging, anti-cancer ‘survival response’ likely in an attempt to extend lifespan. This response suppresses growth and enhances maintenance and defense systems (anti-oxidant defenses, stress resistance, immunological and metabolic parameters) and resembles the longevity response induced by dietary restriction (DR). Remarkably, subjecting the progeroid, dwarf mutants to actual DR resulted in the largest lifespan increase recorded in mammals: thirty percent DR tripled median and maximal remaining lifespan, and drastically retarded all aspects of accelerated aging investigated, but most impressively neurodegeneration, e.g. DR animals retained 50% more neurons and maintained full motoric function, virtually stopping the neuronal decline. Repair-deficient progeroid Xpg-/- mice responded similarly to DR, extending this observation beyond Ercc1. The DR response in Ercc1Δ/- mice resembled DR in wt animals including further reduced IGF1 signaling. Interestingly, ad libitum Ercc1Δ/- liver expression profiles showed preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. These findings strengthen the link between DNA damage and aging, provide insight into the molecular mechanism underlying DR, establish Ercc1Δ/- mice as powerful model for identifying interventions to promote healthy aging, reveal untapped potential for reducing endogenous damage, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases.

In addition, his laboratory pioneered the in vivo analysis of the dynamics of DNA repair by fluorescent tagging in living cells and even living mammalian organisms in combination with local DNA damage induction opening a new field of DNA repair research that explores repair in the most relevant context: the intact organism. Moreover, Hoeijmakers and his team generated the first mammals without a biological clock, and since then also investigated the biological mechanism and clinical impact of the circadian rhythm. In 2005 Hoeijmakers started a company called DNage and in 2012 he founded AgenD whose mission is to provide solutions for medical/health problems associated with aging.

In summary, this pioneering work places DNA damage at the basis of cancer and aging, highlights the flexible nature of aging and establishes the repair mutants as valid tools for identification of life- and healthspan-extending pharmaceutical and nutraceutical interventions in mammals. This opens new avenues for prevention or treatment of aging-related diseases.

Chris Oudmaijer Arts-onderzoeker
Irene van Dijken Phd Student
Ivar van Galen Phd Student
Kimberly Smit Research Technician
Maria Birkisdottir Phd Student
Rutger Ozinga MSc Student
Wilbert Vermeij Post Doc
Willianne Vonk Post Doc
Winnie van den Boogaard OIO
Yvonne Rijksen Technician
Ziqin Tang Phd Student
Contact Information
Jan Hoeijmakers

Jan Hoeijmakers

Oncode Investigator

Oncode Investigator

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