From xeroderma pigmentosum to the biological clock contributions of Dirk Bootsma to human genetics

This paper commemorates the multiple contributions of Dirk Bootsma to human genetics. During a scientific 'Bootsma' cruise on his sailing-boat 'de Losbol', we visit a variety of scenery locations along the lakes and canals in Friesland, passing the highlights of Dirk Bootsma's scientific oeuvre. Departing from 'de Fluessen', his homeport, with his PhD work on the effect of X-rays and UV on cell cycle progression, we head for the pioneering endeavours of his team on mapping genes on human chromosomes by cell hybridization. Next we explore the use of cell hybrids by the Bootsma team culminating in the molecular cloning of one of the first chromosomal breakpoints involved in oncogenesis: the bcr-abl fusion gene responsible for chronic myelocytic leukemia. This seminal achievement enabled later development of new methods for early detection and very promising therapeutic intervention. A series of highlights at the horizon constitute the contributions of his team to the field of DNA repair, beginning with the discovery of genetic heterogeneity in the repair syndrome xeroderma pigmentosum (XP) followed later by the cloning of a large number of human repair genes. This led to the discovery that DNA repair is strongly conserved in evolution rendering knowledge from yeast relevant for mammals and vice versa. In addition, it resolved the molecular basis of several repair syndromes and permitted functional analysis of the encoded proteins. Another milestone is the discovery of the surprising connection between DNA repair and transcription initiation via the dual functional TFIIH complex in collaboration with Jean-Marc Egly et al. in Strasbourg. This provided an explanation for many puzzling clinical features and triggered a novel concept in human genetics: the existence of repair/transcription syndromes. The generation of many mouse mutants carrying defects in repair pathways yielded valuable models for assessing the clinical relevance of DNA repair including carcinogenesis and the identification of a link between DNA damage and premature aging. His team also opened a fascinating area of cell biology with the analysis of repair and transcription in living cells. A final surprising evolutionary twist was the discovery that photolyases designed for the light-dependent repair of UV-induced DNA lesions appeared to be adopted for driving the mammalian biological clock. The latter indicates that it is time to return to 'de Fluessen', where we will consider briefly the merits of Dirk Bootsma for Dutch science in general.

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