About the speakers:
Carlos Conde is an Assistant Professor at the University of Porto and Principal Investigator at the Institute for Research and Innovation in Health (i3S). He completed his postdoctoral training in the laboratory of Professor Claudio Sunkel at the Institute for Molecular and Cell Biology (IBMC, Porto), and joined i3S in 2015 to establish a research program addressing fundamental questions on genome partitioning aiming to better understand why this fails so frequently in Cancer. Carlos is focused on the mechanisms underlying centromere structure, kinetochore-microtubule interactions, spindle orientation and spindle assembly checkpoint signaling and how defects in these processes impact on chromosomal instability and tumorigenesis. To tackle these questions, Carlos and his research group combine in vitro biochemical studies with functional analysis in human cells and Drosophila tissues.
Marin Barisic earned his Diploma 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. After finishing his Postdoc at the Institute for Molecular and Cell Biology in Porto, Portugal, he started his own research group as a Group Leader in the Cell Division and Cytoskeleton lab at the Danish Cancer Institute (DCI) in Copenhagen, Denmark. Work in the Cell Division & Cytoskeleton lab is based on investigation of molecular mechanisms behind chromosomal and cytoskeletal dynamics - the processes whose aberrations during the cell cycle often facilitate tumorigenesis.
Titles and Abstracts:
1. Long distance relationships: how kinetochores and centrosomes talk to each other to promote faithful cell division by C. Conde.
Faithful cell division relies on mitotic chromosomes becoming bioriented with each pair of sister kinetochores bound to microtubules from opposing spindle poles. Erroneous kinetochore-microtubule attachments often form during early mitosis, but are destabilized through the phosphorylation of outer kinetochore proteins by centromeric AURORA B kinase (ABK) and centrosomal AURORA A kinase (AAK), thus allowing for re-establishment of attachments until biorientation is achieved. MPS1-mediated phosphorylation of NDC80 has also been shown to directly weaken the kinetochore-microtubule interface in yeast. In human cells, MPS1 has been proposed to transiently accumulate at end-on attached kinetochores and phosphorylate SKA3 to promote microtubule release. Whether MPS1 directly targets NDC80 and/or promotes the activity of AURORA kinases in metazoans remains unclear. In the seminar, I will present a novel mechanism involving communication between kinetochores and centrosomes, wherein MPS1 acts upstream of AAK to promote error correction. MPS1 on pole-proximal kinetochores phosphorylates the C-lobe of AAK thereby increasing its activation at centrosomes. This proximity-based activation ensures the establishment of a robust AAK activity gradient that locally destabilizes mal-oriented kinetochores near spindle poles. Accordingly, MPS1 depletion from Drosophila cells causes severe chromosome misalignment and erroneous kinetochore-microtubule attachments, which can be rescued by tethering either MPS1 or constitutively active AAK mutants to centrosomes. Proximity-based activation of AAK by MPS1 also occurs in human cells to promote AAK-mediated phosphorylation of the NDC80 N-terminal tail. These findings uncover an MPS1-AAK cross-talk that is required for efficient error correction, showcasing the ability of kinetochores to modulate centrosome outputs to ensure proper chromosome segregation.
2. Unveiling the antimitotic mechanism of parthenolide by M. Barisic.
Parthenolide is a natural compound that has shown highly promising anticancer activity. Even though its mode of action has been studied for decades, its antimitotic activity has been largely overlooked, limiting the understanding of its full anticancer potential. In this study, we combined click chemistry with quantitative mass spectrometry and cell biology to elucidate the mechanism of action of parthenolide in mitosis. We show that parthenolide does not act as a microtubule-targeting agent in cells. Instead, it binds to the kinetochore protein ZNF207/BuGZ, preventing the establishment of proper kinetochore-microtubule attachment. Our results show that parthenolide covalently binds to Cys54 of BuGZ via Michael addition to its α-methylene-γ-lactone moiety. Since Cys54 is located within the second zinc finger domain of BuGZ microtubule-targeting region, we propose that parthenolide interferes with the microtubule-binding ability of BuGZ, consequently preventing kinetochore-microtubule attachments required for accurate chromosome congression to the spindle equator.
About the seminar series
Once a month, NCMM invites international guest speakers to present on topics within molecular life science and medicine.
The seminar is open to all, with no registration needed.
Tea, coffee and a simple lunch will be served at 11.30 before the seminar.
NCMM International seminar schedule for 2024 can be found here.