Hosts: Ian Ganley and Gopal Sapkota

Small Lecture Theatre: Medical Sciences Institute, SLS 

Abstract:  

The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumour progression. Here we show that immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of MHC-I molecules. IRGQ directs misfolded MHC-I towards lysosomal degradation through its unique binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC-I heavy chains do not only accumulate in the cell, but are also transported to the cell surface, thereby promoting an immune response. Accordingly, mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels, due to increased reactivity of CD8+ T cells towards IRGQ knock-out tumour cells. Thus, we reveal IRGQ as a novel regulator of MHC-I quality control, mediating tumour immune evasion.  

Bio:  

Lina undertook her joint undergraduate studies in Applied Biology and Molecular Biology at the Hochschule Bonn-Rhein-Sieg (Germany) and University of Dundee (UK), respectively. For her Ph.D. research with Prof. Gopal Sapkota at the MRC Protein Phosphorylation and Ubiquitylation Unit in Dundee, Lina worked on identifying and characterising deubiquitylating enzymes regulating the TGF-beta and BMP signalling pathways. Lina was awarded the EMBO fellowship to pursue her postdoctoral research with Prof. Ivan Dikic to work on linear ubiquitylation and autophagy. Lina is currently a group leader within the Immune Signalling program at the Institute of Biochemistry II at Goethe University and her research focusses on the interplay between immune signalling and autophagy in the context of tumour progression. 

Suzi Gasparini will share the processes and practices that she has  developed over the past few years to facilitate young people’s transitions to, and through, secondary school.

Suzi is Acting Depute Head Teacher (Inclusion) at Craigie High School, Dundee. She brings a wealth of knowledge from her career in Further Education as a lecturer within the Supported Learning Department, and then teaching children experiencing additional support needs (ASN) within both primary and secondary schools. Her career has always been focused on her interests, which are ASN, attainment and transitions. She has written for the SQA, as part of the National 2 team.

Suzi will be in conversation with Divya Jindal-Snape, who also undertakes transitions and inclusion research.

Host: Professor Alessio Ciulli  

Venue: MSI, Small Lecture Theatre, SLS

Abstract:

The cell cycle is a tightly regulated process governing cell growth, duplication of genetic material, and cell division. Progression between cell-cycle phases relies on core machinery within the nucleus. Transition between subsequent phases is associated with the activity of core cell cycle machinery, cyclins and cyclin-dependent kinases (CDKs), which phosphorylate cellular proteins, thereby propelling cell cycle progression. Importantly, some of these components, which are not essential in postnatal life, have been shown to be required for initiation and maintenance of various cancers in mice. Consequently, targeting cell-cycle proteins appears effective in halting tumor growth and is an area of active investigation.

The transition of mammalian cells from growth (G1) into the DNA synthesis (S) phase, often referred to as G1/S transition, marks a critical step in cell cycle progression. This process has long been thought to hinge on the activity of a kinase called CDC7, a vital initiator of DNA replication, working in tandem with CDK2. However, our latest research reveals a groundbreaking twist: CDC7 is not as indispensable as once believed. Through innovative chemical genetic and targeted protein degradation techniques, we have explored the role of CDC7 in various cell types, both in laboratory tissue cultures and living mice. We found that CDC7 and another kinase, CDK1 (classically associated with regulating mitosis), have overlapping functions in initiating DNA replication. In essence, either of these kinases can facilitate the entry into the S phase, challenging previous assumptions about their distinct roles. From a methodological standpoint, this work constituted the first use of targeted protein degradation to study the function of an endogenous protein in a living animal.

Bio

I earned my PhD in 2013 within an international program funded by the Foundation for Polish Science. I conducted my research at the Nencki Institute of Experimental Biology in Warsaw, Poland and the University of Ferrara in Italy. My PhD work focused on the implications of mitochondrial dysfunction on cellular physiology, particularly investigating the role of mitochondrial uncoupling proteins (UCPs) in mitigating oxidative stress, as well as mitochondrial roles in cell signaling and oligodendrocyte progenitor differentiation. I also developed a method for isolating plasma membrane-associated microdomains, important for studies on cellular signaling.

From 2014 I furthered my research during postdoctoral training at Dana-Farber Cancer Institute in Boston under the supervision of Professor Peter Sicinski. There, I explored the molecular functions of core cell cycle machinery in DNA replication initiation. Pioneering a novel approach, I developed a mouse model enabling the chemical depletion of specific proteins, a breakthrough in studying protein functions in vivo. This work led to the re-evaluation of the role of CDC7 in DNA replication and the discovery of its functional redundancy with CDK1, offering new insights into cell cycle regulation and potential cancer treatments.

Since 2022 I am a Senior Scientist within the Tumor Drivers and Resistance group at AstraZeneca in Boston where I develop scientific strategy and technology and provide hands-on support for projects at different pre-clinical stages. At AZ, I chair a “New Targets” Forum, aiming to identify new therapeutic opportunities against cancer.