Cell Division and Cytoskeleton
Current work in the Cell Division and Cytoskeleton group is focused on investigation of molecular mechanisms of chromosomal and cytoskeletal dynamics, whose alterations during the cell cycle promote aneuploidy and metastasis, and consequently facilitate tumorigenesis.
Our Research
Microtubules are key components of cytoskeleton that enable intracellular transport, thus contributing to essential cellular functions, including cell division and migration. Microtubules are important drug target of anticancer agents, such as the vinca alkaloids and taxane. However, due to various side effects, such as neuropathies and neurotoxicity, as well as due to the development of drug resistance, the efficacy of these drugs are often challenged in clinical settings.
Consequently, specific targeting of other molecules or molecular properties involved in microtubule-related functions is of great interest. These include tubulin PTMs and tubulin isotypes, which together compose the so-called “tubulin-code”.
Tubulin detyrosination is one of the tubulin PTMs that is altered in different cancers and its dysregulation is associated with tumor aggressiveness and poor prognosis in patients, making it a highly promising “molecular target”. In addition, numerous motor proteins are deregulated in cancer and the inhibitors of some of those are involved in advanced phases of clinical trials. Because of the impact of tubulin PTMs on the activity of motor proteins, as well as their association with cancer, this still underexplored field is a particularly attractive platform for the quest for potential anticancer therapeutics.
Our research is highly based on investigation of
- mechanisms of chromosome congression and segregation during mitosis
- regulation of microtubule dynamics
- the impact of tubulin PTMs on the activity of cytoskeletal motor proteins and their roles in chromosomal and cellular movements
Recently, our work contributed to solving the first structure and elucidating the mitotic role of a recently identified tubulin carboxypeptidase, the vasohibin-SVBP complex (Liao, Rajendraprasad et al., Cell Res 2019). We also established the long-sought molecular mechanism and role of microtubule poleward flux (Steblyanko et al., EMBO J 2020).
Steblyanko Y, Rajendraprasad G, Osswald M, Eibes S, Jacome A, Geley S, Pereira AJ, Maiato H, Barisic M: Microtubule poleward flux in human cells is driven by the coordinated action of four kinesins. EMBO J 2020;e105432
Liao S, Rajendraprasad G, Wang N, Eibes S, Gao J, Yu H, Wu G, Tu X, Huang H, Barisic M, Xu C: Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis. Cell Res 2019;29(7):533-547
Barisic M, Silva e Sousa R, Tripathy SK, Magiera MM, Zaytsev AV, Pereira AL, Janke C, Grishchuk EL, Maiato H: Microtubule detyrosination guides chromosomes during mitosis. Science 2015;348(6236):799-803
Barisic M, Aguiar P, Geley S, Maiato H: Kinetochore motors drive congression of peripheral polar chromosomes by overcoming random arm-ejection forces. Nat Cell Biol 2014;16(12):1249-1256
Barisic M, Sohm B, Mikolcevic P, Wandke C, Rauch V, Ringer T, Hess M, Bonn G, Geley S: Spindly/CCDC99 is required for efficient chromosome congression and mitotic checkpoint regulation. Mol Biol Cell 2010;21(12):1968-1981
Group Leader: Marin Barisic
Marin Barisic has earned his Master’s degree in Molecular Biology at the University of Zagreb in Croatia, and his PhD in Molecular Cell Biology and Oncology at the Innsbruck Medical University in Austria.
During his PhD studies in the laboratory of Dr. Stephan Geley, Marin has developed a strong interest in exploring the molecular mechanisms that ensure accurate cell division and identified human Spindly as an essential kinetochore adaptor of motor protein Dynein and important component of the mitotic checkpoint pathway (Barisic et al., Mol Biol Cell 2010).
During his postdoctoral stay in Helder Maiato’s lab, Marin has further improved his interest and skills in advanced live cell imaging and applied it to determine how multiple motor proteins with opposite polarities coordinate their activities to drive chromosome congression (Barisic et al., Nat Cell Biol 2014). He showed that Dynein poleward force counteracts chromokinesins to prevent stabilization of immature/incorrect end-on kinetochore-microtubule attachments and random ejection of polar chromosomes, revealing a previously overlooked role of Dynein in prevention of errors that could lead to aneuploidy.
As a follow up from this study, he and his colleagues revealed that kinetochore motors are guided by microtubule detyrosination (Barisic et al., Science, 2015). This important finding provided evidence for the existence of a navigation system for chromosomes during mitosis that is based on tubulin post-translational modifications (PTMs), answering a critical longstanding question how chromosomes are biased towards the cell equator prior to their segregation.
Marin is currently head of the Cell Division and Cytoskeleton group at the Danish Cancer Society Research Center, where he studies the molecular mechanisms behind chromosomal and cytoskeletal dynamics, with a special focus on the roles of motor proteins and tubulin PTMs.
ORCID: 0000-0001-7587-3867
Key Funding
Lundbeck Foundation
Danish Cancer Society Scientific Committee
Novo Nordisk Foundation