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Hoeijmakers, Jan

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MScMM faculty - Jan HoeijmakersJan H.J. Hoeijmakers studied biology at Nijmegen University, the Netherlands. His PhD work on trypanosomes at the University of Amsterdam (supervisor P. Borst), resolved the structure and main function of the kinetoplast DNA network, the curious mitochondrial DNA of these parasites with the shape of a fishnet. In addition, he elucidated the molecular basis for the enigmatic, medically very important mechanism of antigenic variation by which trypanosomes switch each time surface coats and thereby escape from immune surveillance causing sleeping sickness. His discovery of complex gene rearrangements and duplication-transposition of one gene copy to an expression site was one of the first genome rearrangements ever reported and provided the basis for a research line that still continues.

After his PhD (1981) he joined the Institute of Genetics of the Erasmus University (head D. Bootsma) to work on DNA repair and genome stability in mammals. He cloned the first of many subsequent human DNA-repair genes and discovered the strong evolutionary conservation of DNA repair systems in general. This provided the basis for the elucidation of the reaction mechanism of nucleotide excision repair (NER). In addition he resolved the molecular basis of a number of human NER syndromes, which present a perplexing clinical heterogeneity ranging from extreme cancer predisposition as in xeroderma pigmentosum to dramatic neurodevelopmental abnormalities with no cancer as in Cockayne syndrome and trichothiodystrophy (TTD). His discovery (together with J-M Egly) that basal transcription factor TFIIH is at the same time involved in opening the DNA for NER led to the novel concept of 'basal transcription syndromes', explaining part of the complex TTD phenotype.

In the past period of 10 years his team made many seminal contributions to the field of genome stability. He resolved the function of key factors in NER, such as the endonuclease role of the ERCC1/XPF complex, the discovery that the XPC complex is the primary damage recognition factor and the finding of a novel mechanism of regulation of NER by DNA damage. Also the dynamic aspects and organization of DNA repair in living cells were pioneered using proteins provided with a fluorescent tag, sophisticated laser-directed photobleaching and local damage induction techniques and time-resolved analysis of protein mobility (work involving Co-PI W. Vermeulen). This revealed the dynamic organization of DNA repair in living cells: free diffusion of individual DNA repair factors throughout the nucleus and ordered transient assembly at sites of DNA damage. To understand the medical and biological impact of DNA repair in intact organisms knock-in mice were generated in which specific DNA factors are labelled by a fluorescent protein, permitting for the first time analysis of DNA repair parameters in all organs and tissues of an intact organism. Furthermore, his laboratory generated the most extensive collection of mouse models for human repair deficiencies (work involving Co-PI Dr. G. van der Horst).

Several mice carry precisely the same point mutations as found in human NER patients and display a striking similar phenotype. The mouse mutants have proven extremely valuable for understanding the impact of DNA damage and repair on carcinogenesis and mutagenesis and revealed an unexpected very strong link with aging. A striking correlation was found between the extent of the repair defect and the severity of premature but bona fide aging; in several mutants limiting life span to only 3 weeks. This uncovered a trade-off between cancer and aging dependent on the type of DNA damage and specific repair processes, whether or not the repair system promotes survival after DNA damage, thereby postponing aging, but enhancing the risk of mutations and cancer. Conditional mutants allowed accelerated aging to be targeted to specific organs/tissues or stages of differentiation (e.g. mouse mutant exhibiting dramatic aging only in the brain), making aging amenable to manipulation. Using expression profile analysis a powerful ‘survival response’ was identified in rapidly aging mouse mutants, that is able to redirect resources from growth and proliferation to protection, maintenance and repair, when unfavourable conditions are met. This response promotes successful aging, counteracts cancer, can be triggered by persistent DNA damage and is cell autonomous. The first mice with a complete inactivation of the biological clock, which controls metabolism and physiology generated in his laboratory provided unexpected evidence for a link with DNA damage and aging (work involving CoPI G. van der Horst). These findings have a profound impact on understanding the molecular basis of ageing. Currently this project translates into important applications such as identification of biomarkers and compounds which are able to prevent or postpone many aging-related diseases, including cancer.

His team owns several patents in genome stability and the relation with aging. To accomplish these objectives that address the main medical challenges of developed societies he started in 2004 a spin-off company called ‘Dnage’. The knowledge accumulated as the result of this work is of general significance for understanding the origin of carcinogenesis, genotoxicity, inborn disorders and the process of ageing and thereby is relevant for the major medical needs of developed societies.

In 2011, Jan Hoeijmakers (together with Bert Vogelstein) was awarded the Cancer Research Prize of the Charles Rudolph Brupbacher Stiftung (Zürich), for research on the role of genome stability on cancer and aging. Also in 2011, he was appointed KNAW Academy Professor as a lifetime achievement award. In 2013, Jan Hoeijmakers received knighthood in the Order of the Netherlands Lion.

Department of Molecular Genetics website

 

Publications 

Hoeijmakers JH (2009)
DNA Damage, aging, and cancer
NEJM 361:1475-1485

Garinis GA, van der Horst GT, Vijg J, and Hoeijmakers JH (2008)
DNA damage and aging: new-age ideas for an age-old problem
Nature Cell Biology 10:1241-1247

Niedernhofer LJ, Garinis GA, Raams A, Lalai SA, Robinson RA, Appeldoorn E, Odijk H, Oostendorp R, Ahmad A, van Leeuwen W, A. Theil, Vermeulen W, van der Horst GT, Meinecke P, Kleijer W, Vijg J, Jaspers NGJ and Hoeijmakers JH (2006)
A new progeriod syndrome reveals that genotoxic stress suppresses the somatotroph axis
Nature 444:1038-1043 (see also accompanying ‘News and Views’, Kirkwood)

Lans H and Hoeijmakers JH (2006)
Cell Biology: aging nucleus gets out of shape
Nature 440:32-34 

Andressoo JO, Jans J, de Wit J, Coin F,, Hoogstraten D, van de Ven M, Toussaint W, Huijmans J, Thio HB, van Leeuwen WJ, de Boer J, Egly JM, Hoeijmakers JHJ, van der Horst GTJ, Mitchell JR (2006)
Rescue of progeria in trichothiodystophy by homozygous lethal Xpd alleles
PLoS Biol. Oct;4(10):e322

Niedernhofer LJ, Lalai AS, Hoeijmakers JH (2005)
Fanconi anemia (cross)linked to DNA repair
Cell 123, 1191-1198 (Review)