CDC7-independent G1/S transition revealed by targeted protein degradation

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.