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 Hoeijmakers team cloned 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 elucidated the molecular basis of the cancer-prone repair disorder xeroderma pigmentosum (XP) and the -till then enigmatic- neurodevelopmental repair conditions, Cockayne syndrome (CS) and trichothiodystrophy (TTD). His team identified the XPC protein as the key DNA damage recognition factor, the 10-subunit TFIIH complex as local unwinding component and the ERCC1/XPF endonuclease involved in damage excision. He was the first to synthesize the outline of the nucleotide excision repair (NER) reaction mechanism. In addition, the Hoeijmakers 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. This opened a new field of DNA repair research that explores repair in the most relevant context: the living cell and intact organism. Subsequently, his team embarked upon the systematic generation of a series of mouse repair mutants, to bridge the gap between cells and patients. The mouse mutants turned out to be extremely informative: they mimicked the corresponding human syndromes to an exceptional degree and enabled detailed insight into the complex aetiology of human repair diseases, including the initially highly controversial identification of many features of accelerated, but fully bona fide aging. 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 such as the hematopoietic system. Conditional repair mutants allowed 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 hypomorphic Ercc1^Δ/-mutant, affected in 4 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 behavioural-physiological-hormonal alterations, loss of stem cells, increased cellular senescence, overall frailty and gene expression patterns alike natural aging. Importantly, this mutant is found to be a superior model for Alzheimer and other neurodegenerative disease addressing a tremendous unmet medical need, fully consistent with the notion that aging is the most important risk factor for all these proteinopathies.

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 response likely in an attempt to extend lifespan. This ‘survival’ response suppresses growth and enhances maintenance and defence systems (anti-oxidant defences, stress resistance, immunological and metabolic parameters) and -interestingly- resembles the anti-aging longevity response induced by calorie restriction (CR). Strikingly, subjecting the progeroid, dwarf mutants to actual CR resulted in the largest lifespan increase recorded in mammals: 30% CR tripled median and maximal remaining lifespan, and drastically retarded all aspects of accelerated aging investigated, but most impressively neurodegeneration. CR animals retained 50% more neurons, maintained full motoric function, and even lost tremors not only arresting neuronal decline, but even improving neurofunctioning. Repair-deficient progeroid Xpg^-/- mice responded similarly to CR, extending this observation beyond Ercc1. The CR response in Ercc1^Δ/- animals resembled CR in wt, except that the unfolded protein response (UPR), which is already highly upregulated in ad libitum Ercc1^Δ/- mice was tempered by CR. Importantly, ad libitum Ercc1^Δ/- liver showed a progressive dramatic decline of overall transcription, preferentially of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. This lowered and imbalanced transcriptional output was subsequently also discovered in normal aging in numerous post-mitotic tissues in many species including humans, and appeared even present in C.elegans, demonstrating its universal occurrence and stressing the value of progeroid repair-deficient mutants for normal aging. Moreover, this phenomenon of transcription stress was shown to be the direct consequence of DNA damage blocking elongating RNA polymerase and to explain a major part of all aging-related expression changes in many (post-mitotic) organs and tissues. As transcription is essential for all cellular processes, DNA-damage-driven transcription stress affects numerous cellular processes, found to change with aging, revealing how accumulation of DNA damage causes aging in most of the soma. CR largely prevented this decline of transcriptional output, indicating that CR reduces DNA damage levels and prolongs genome function and revealing how CR delays aging. These findings strengthen the link between DNA damage and aging, provide insight into the molecular mechanism underlying CR, establish Ercc1^Δ/- mice as powerful model for identifying interventions to promote healthy aging, reveal untapped potential for reducing endogenous damage, and suggest a counterintuitive CR-like therapy for human progeroid genome instability syndromes and CR-like interventions for preventing neurodegenerative diseases. Indeed, reducing calorie intake in CS and TTD children, which normally get extra nutrition as they are severely growth-retarded, induced dramatic improvements, most spectacularly in neurological performance, and most likely extends life expectancy, constituting the first therapeutic intervention for these dramatic syndromes. This stresses the clinical importance and the validity of the findings in the corresponding mouse mutants.

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, including cancer.

Summary Breakthrough Discoveries in DNA Repair

• Molecular cloning of the first mammalian DNA repair gene, followed by approximately half of nucleotide excision repair (NER) and transcription-coupled repair genes, discovery of the very strong evolutionary conservation of DNA repair and delineation of functional properties.
• Resolving the molecular basis of human DNA repair disorders xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy.
• Discovery of the connection between transcription initiation and DNA repair and identification of a novel clinical entity: transcription syndromes.
• Identification of XPC as the initiator of global genome NER.
• First to delineate the correct outline of the NER reaction mechanism in eukaryotes
• Development of technologies to study DNA repair in living cells and intact mice, discovery of the highly dynamic nature of DNA repair in vivo and sequential assembly of repair factors.
• Generation of the most extensive series of DNA repair mouse mutants as exemplary models for the corresponding human DNA repair syndromes.
• Discovery of the role of mammalian photolyase paralogs Cry1 and Cry2 in the circadian rhythm by generating the first mammals without biological clock.
• Discovery of the very strong connection between the DNA damage response and aging and identification of DNA damage as the main cause of systemic aging and aging-related diseases.
• Generation of the best (accelerated) aging mouse models for molecular, cellular, organismal aging and for anti-aging interventions.
• Discovery that calorie restriction reduces cellular DNA damage, explaining part of its general anti-aging, lifespan-extending effect.
• Identification of transcription stress as a novel mechanism underlying aging in post-mitotic organs and tissues explaining all proteinopathies and aging as the main risk factor in dementias.
• Identification of nutritional interventions for effective treatment of human DNA repair syndromes exhibiting accelerated aging.
• Discovery of the powerful anti-aging ‘survival response’ induced by short-term fasting and calorie restriction and its protection from ischemia reperfusion injury associated with surgery, and organ transplantation and from chemo- and radiotherapy, impacting major areas in Medicine.