From basic science to industrial exploitation

We will optimise cancer diagnosis and treatment

We are a doctoral network focused on understanding how DNA replication shapes cell fate and determines cancer development. Our work will identify unexpected targets within the replication machinery resulting in novel therapeutic approaches in cancer and other diseases.

Traditionally, alterations in DNA replication have been interpreted as a consequence of modifications in the transcriptional status of the cell, the structure of chromatin or the response to stress. Our proposal represents a paradigm shift in which modulating DNA replication is the means and not the consequence of chromatin changes that underlie cell fate and cancer development.

A multi-perspective strategy

Different approaches to
understand DNA replication

Our research program is articulated in four interconnected but independent work packages (WP)
that converge to characterize DNA replication as a driver of cell fate decisions.

WP1 – Understand

DNA replication mechanism dealing with stress

Using biochemical, molecular, and structural studies, we will reveal how the process of
DNA replication is modified to enable cells to answer to genotoxic and endogenous stresses.

Regulation of DNA replication by PTMs
during cell fate decisionss
Identification of novel ubiquitin/SUMO ligases involved in the DNA damage response/replication stress
PTM regulation of replication stress
responses with implications for ALT
and PARPi sensitivity

WP2 – Drive

DNA replication determining cell fate

Through the development of new imagine techniques, genetic perturbations, and integrative functional genomics, we will test if the DNA replication by itself drives the process of cell differentiation.

Replisome composition as a driver of cell differentiation and malignant transformation
Replication dynamics, nascent transcription and chromatin conformation changes upon cell commitment
Analysis and role of replication features in early mouse embryos and during reprogramming to totipotency

WP3 – Respond

DNA replication mediating inflammatory response

By combining microfluidics, proteomics, and live imaging, we will identify the nature of cytosolic DNA in cells exposed to genotoxic agents and to dissect the role of interferon signaling in DNA replication, replication stress and chemo-resistance.

Characterization of immunogenic
cytosolic DNA species induced by
DNA replication stress (RS)
Licensing system aberrations: from replication stress to inflammation
Role of Interferon and of ISG15
system in DNA replication

WP4 – Target

DNA replication targets for cancer therapeutics

Employing chemical biology, state-of-the-art screenings, animal models and drug development, we will exploit DNA replication alterations occurring in cancer cells to identify and develop new treatment strategies.

Relevance of FRA3B/FHIT
loss in tumorigenesis
Exploring the genetic space
of replication proteins
Discovery of small molecule modulators of human PLK1-Interacting Checkpoint Helicase PICH1 and Ubiquitin-E3_LigaseTRIP12