Research focus The Genome Integrity research focuses on deciphering the intrinsic functions of homologous recombination (HR) which has a dual role in the maintenance of genome stability. First, it promotes the faithful repair of DNA double-strand breaks belonging amongst the most lethal forms of DNA damage. Moreover, HR is also required for stabilizing stalled replication forks, promoting their reversal, protection and restart to ensure completion of replication and ensure genome maintenance. Inability to perform and regulate recombination is linked to human infertility, miscarriage and genetic diseases, particularly cancer, this further emphasizes the importance of a better mechanistic understanding of this pathway. Furthermore, the GENI team focuses on the detailed study of nucleases, which comprise an integral part of many DNA repair pathways and their inactivation leads to genomic instability and cancer.
• Characterizing the mechanism and regulation of homologous recombination and its intrinsic role in the maintenance of genome stability.
• Mechanistic understanding of the action of HR co-factors and their impact on genome integrity and cancerogenesis.
• Development of potent and selective inhibitors of nucleases for possible therapeutic use.
• Francis Crick Institute, London, UK
• University of Zurich, Zurich, Switzerland
• IFOM, Milan, Italy
Offered services and expertise
• Various methods from biochemistry, structural biology, molecular biology, genetics and biophysics.
• Detailed studies of protein properties and activities including their interactions with other molecules such as DNA and small molecule inhibitors.
KOLINJIVADI, AM, SANNINO, V, DE ANTONI, A, Zadorozhny, K, Kilkenny, M, Techer, H, Baldi, G, Shen, R, Ciccia, A, Pellegrini, L, Krejci, L*, Costanzo, V. (2017) Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments. Mol Cell. 67 (5): 867658.
DI MARCO, S, HASANOVA, Z, KANAGARAJ, R, CH, N, ALTMANNOVA, V, MENON, S, SEDLACKOVA, H, LANGHOFF, J, SURENDRANATH, K, HUHN, D, BHOWMICK, R, MARINI, V, FERRARI, S, HICKSON, ID, KREJCI, L*, JANSCAK, P. (2017) RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis. Mol Cell. 66 (5): 658-+. DOI: 10.1016/j.molcel.2017.05.006. IF= 14.248
TAYLOR MR, ŠPÍREK M, JIAN MA C, CARZANIGA R, TAKAKI T, COLLINSON LM, GREENE EC, KREJCI L*, BOULTON SJ. (2016) A Polar and Nucleotide-Dependent Mechanism of Action for RAD51 Paralogs in RAD51 Filament. Mol Cell. 64 (5): 926-939
TAYLOR, M., ŠPÍREK, M., CHAURASIYA, K., WARD, J., CARZANIGA, R., YU, X., EGELMAN, E., COLLINSON, L., RUEDA, D., KREJČÍ, L., BOULTON, S. Rad51 Paralogs Remodel Pre-synaptic Rad51 Filaments to Stimulate Homologous Recombination. Cell. 2015, 162(2), 271-286.
KREJCI, L.*, VAN KOMEN, S., LI, Y., VILLEMAIN, J., REDDY, M. S., KLEIN, H., ELLENBERGER, T., SUNG, P. (2003) DNA helicase Srs2 disrupts the Rad51 presynaptic filament. Nature 423:305-9.
Other selected results
Several studies deciphering the essential role of post-translational modification SUMOylationand its effect on the function of various HR proteins.
Discovery of the mechanism how Rad51 paralogs stimulates the function of Rad51 during HR.
INTERNATIONAL CLINICAL RESEARCH CENTER
OF ST. ANNE’S UNIVERSITY HOSPITAL BRNO