When DNA replication runs into a problem

Hematology Seminar by Puck Knipscheer

Erasmus Medical Center, Department of Hematology 19-1-2015

At the moment, Puck Knipscheer is the group leader of the Knipscheer research group at the Hubrechts Institute Utrecht. This group is currently trying to get a better understanding of the so called Fanconi Anemia pathway (FA pathway).  This pathway plays an important role in the DNA repair mechanism that repairs interstrand crosslinkings (ICLs). As can be seen in figure 1, interstrand crosslinking (ICL) is the phenomenon that the two strands of DNA are linked together and can be induced by exo- and endogenous agents such as carmustine and nitrogen mustard, which are agents used in chemotherapy. This means that understanding interstrand crosslinking and its repair mechanisms could be and already is very useful in treatment of cancer.

Your body, and that of many other animals, has a repair mechanism to repair interstrand cross links and as said, the FA pathway plays an important role in this. What the FA pathway basically does is coordinating and initiating several DNA repair mechanisms. This is done by the ubiquitination of the proteins FANCI and FANCD2, who in their turn activate other repair mechanisms like homologous recombination, nucleotide excision repair and mutagenic translesion synthesis. People who have a mutation in their DNA that prevents the pathway from being executed suffer from the genetic disease Fanconi Anemia (FA). These people have several symptoms, like developmental defects, bone marrow failure, increased cancer risks and cellular sensitivity to ICLs. Understanding the pathway, like Puck Knipscheer aims to do, can therefore contribute to both cancer treatments as well as understanding and perhaps healing of FA. DNA replication and repair is studied Xenopus Laevis (African clawed frog) egg extracts, because they are known to have unique form eukaryotic DNA replication and are fully soluble.

Kasper Spoelstra – wkspoelstra@hotmail.nl


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