DNA Damage and Repair

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 together with XPG 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 mice 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 mammal.

Simultaneously, his team embarked upon the systematic generation 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 etiology of human repair diseases, including the initially highly controversial identification of many features of accelerated, but fully bona fide aging. This disclosed a balance between cancer and aging and the link of both with DNA damage.