Jan H.J. Hoeijmakers Genome Stability, Cancer and Aging
PhD: University of Amsterdam (on kinetoplast DNA and antigenic variation of trypanosomes, supervisor Piet Borst, 1982)
Postdoc and subsequent scientific career: Dept. Molecular Genetics, Erasmus Medical Center Rotterdam
Our interest is understanding the clinical impact of DNA damage, which is continuously inflicted by exogenous and endogenous agents onto our genes. To that aim we focused on DNA repair. We cloned the first and subsequently ~half of all genes involved in mammalian nucleotide excision and transcription-coupled repair, resolved the molecular basis of the corresponding rare human DNA repair disorders xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy and identified human syndromes in basal transcription. By pioneering DNA repair in living cells and intact mice, we disclosed the dynamic nature of repair in vivo. These advances paved the way for elucidation of the underlying repair mechanism. To study the consequences of DNA damage at the level of an intact mammal, we generated the largest set of mouse repair mutants and discovered that a specific subset of these mutants displayed many bona fide features of aging, but in an accelerated form. These mice turned out excellent models for the human disorders, allowed us to discover an anti-aging ‘survival response‘ which prioritizes resilience mechanisms above growth and to identify DNA damage and transcription stress as the main cause of aging. Surprisingly, dietary restriction was found to dramatically delay accelerated aging in the mouse repair mutants by reducing DNA damage, revealing one way by which nutrition can counteract aging. Applying these findings to the first human patients yielded spectacular improvements, most impressively regarding neurofunction and have led to new guidelines for nutritional care. These findings have far-reaching clinical implications for many aging-related diseases particularly neurodegeneration, for reducing side effects of chemo- and radiotherapy, and of ischemia reperfusion injury associated with surgery and organ transplantation. The future mission of our research is translation of the above findings to as many clinical applications as possible.
Jan Hoeijmakers heads research teams in the Erasmus Medical Center, the Princess Máxima Center for Pediatric Oncology in Utrecht and the CECAD in Cologne. He has obtained many (inter)national awards and distinctions for his scientific achievements including the Spinoza award, Louis Jeantet Prize for Medicine in Europe, the Josephine Nefkens Prize for cancer research, two ERC advanced grants and an ERC PoC grant, the Koningin Wilhelmina Research Prize of the Dutch Cancer Society and recently the Thon Award of the Olav Thon Stiftelsen (Oslo).