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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

Via Vincenzo Vela 6 - CH-6500 Bellinzona
Tel. +41 91 820 0300 - Fax +41 91 820 0302 - info [at] irb [dot] usi [dot] ch

Recombination Mechanisms

Petr Cejka, Group Leader

Roopesh Anand, Elda Cannavò Cejka, Ilaria Ceppi , Sean Michael Howard, Lepakshi , Giordano Reginato

Deoxyribonucleic acid (DNA) stores genetic information that contains instructions for the proper development and function of all living organisms. The integrity of DNA must be preserved during the life cycle in order to maintain cellular functions and to pass information encoded in it onto the next generation. It has been estimated that each cell in a human body acquires tens of thousands of DNA lesions per day. The sources of DNA damage may stem from the environment, such as sunlight or chemicals, or result from regular cellular processes such as metabolism. These events represent a major challenge: if left unrepaired, the lesions could block access to the genetic information and prevent faithful replication (copying) of the DNA molecule. On the other hand, incorrect repair may lead to mutations (changes in genetic information) or chromosomal aberrations (larger scale rearrangements of genetic material). These events may threaten cell viability or, in some cases, result in uncontrolled cell division (cancer).

Throughout evolution, cells have evolved a number of DNA repair pathways specialized for the various classes of DNA damage. Our interest in these mechanisms is stimulated by the fundamental importance these processes play in life. Many DNA repair factors are essential for viability – cells cannot exist without them. Others are important only in special cases - hereditary or sporadic defects in some components of the repair machinery lead to a variety of syndromes characterized by premature aging, cancer predisposition or other abnormalities. Finally, the efficiency of DNA repair mechanisms often affects cancer chemotherapy: a number of drugs that are being used to treat cancer act by causing DNA damage. The mechanisms of action of these drugs as well as repair strategies are often not well understood.

Our research group is interested in DNA repair mechanisms from a basic research standpoint: we want to learn how these pathways operate in healthy cells and how defects lead to abnormalities and disease. Specifically, we focus on a DNA repair pathway termed homologous recombination. Homologous recombination is a highly intricate complex of processes, which repairs breaks in DNA strands. Most cells contain more than one copy of genetic information in each cell, and homologous recombination can exploit that in a very elegant manner. It can restore the integrity of the damaged DNA molecule by using genetic information stored in the identical (or homologous) copy of DNA. This process may thus restore DNA integrity in a largely accurate manner. Homologous recombination is highly conserved in evolution: the mechanism in the bacterium Escherichia coli or in the yeast Saccharomyces cerevisiae is very similar to the mechanism in human cells. This observation underlines the fundamental importance of this pathway in all kingdoms of life. Also, by using the simple organisms as research models, we can learn about homologous recombination in an experimentally more feasible setup. Our research group is using both Saccharomyces cerevisiae and human systems.

Currently, we are using mostly biochemical methods to answer fundamental questions in biology. We express and purify recombinant proteins, assemble multiprotein complexes, and analyze their behavior on synthetic structures that mimic their physiological substrates. Genetic and cell biological techniques are suitable to identify components of new or existing pathways and phenotypic analysis often infers a specific function, yet it becomes limiting when trying to elucidate detailed molecular mechanisms. Redundant and overlapping pathways often further complicate interpretation of in-vivo based experiments. Biochemical analysis is in contrast very powerful to explain underlying molecular mechanisms.