On Tuesday, July 3th, 2007 Paul-André Genest will defend his thesis titled “Analysis of the modified DNA base J and the J-binding proteins in Leishmania” in order to obtain the doctorate degree from the University of Amsterdam. His promoter is Professor Piet Borst.
Leishmania sp, is a protozoan parasite that is transmitted by the phlebotomine sandfly and infects 12 million people worldwide. The genome of Leishmania and other closely related protozoans contains an unusual hypermodified DNA base named J, or b-D-glucosyl-hydroxymethyluracil, which was discovered in the laboratory of Piet Borst at the NKI in 1993.
Over the years, the group of Piet Borst generated substantial evidence that J is synthesised in two steps: 1) First, a thymine in DNA is converted to hydroxymethyluracil (HMU) by a thymidine hydroxylase. 2) Second, a glucosyl transferase converts HMU into J. Attempts to isolate these enzymes had previously not been successful. The laboratory of Piet Borst identified, however, a protein that binds to J in double-stranded DNA. This protein was named JBP1 for the J-binding protein 1. Moreover, a JBP1 homolog was identified by an in silico screen and this was named JBP2.
In his thesis, Paul-André Genest presents evidence that JBP1 and JBP2 might both be thymidine hydroxylases involved in the first step of J synthesis. Paul-André also tried to inactivate by gene targeting JBP1 and JBP2 in Leishmania. His data show that JBP2 is dispensable for the survival of Leishmania, whereas JBP1 is essential. This makes JBP1 an interesting target for an eventual anti-leishmanial drug, since JBP1 is not found in human.
Paul-André also looked at the location of the modified DNA base J in the genome of Leishmania and found that over 95 % of J is found in the telomeric repeats, which are DNA sequences located at the end of the chromosomes. This suggests that J might play a role in the telomere biology of Leishmania.
The thesis defence is open to the public.
Location: Agnietenkapel of the University of Amsterdam
Date: Tuesday July 3th at 14.00 hours