Research

The maintenance of genome stability relies on the accurate and processive replication of genomic DNA and its dysregulation triggers genomic instability, a major hallmark of cancer.

Cancer cells are indeed characterised by a constitutive defective DNA replication, also known as replication stress, whose nature is still poorly characterised. Understanding how cancer cells perturb their chromosomal DNA replication, while increasing our knowledge of the causes and consequences of genomic instability in cancer, might also pave the way to the identification of synthetic vulnerabilities of cancer cells and novel therapeutic approaches.

My lab is interested in understanding the basic mechanisms that coordinate initiation and progression of DNA replication in mammalian cells, the links with the machinery that assembles nucleosomes at the replication fork and how dysfunctional DNA replication triggers genomic and epigenomic instability in cancer.

Thus, we combine classical cell biology and biochemistry, with state-of-the-art genomic and proteomic approaches to identify and characterise new factors involved in the maintenance of genome and epigenome stability at the replication forks and to search for novel vulnerabilities of cancer cells.

Major Funding

• 2020-2023 - Barts Charity, Roles of DNA Polymerase Epsilon in the maintenance of genetic and epigenetic stability.

Recent Publications

Multiple roles of Pol epsilon in eukaryotic chromosome replication Cvetkovic MA, Ortega E, Bellelli R et al. Biochemical Society Transactions (2022) 50(7) 309-320

Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD Hewitt G, Borel V, Segura-Bayona S et al. Molecular Cell (2021) 81(7) 767-783.e11

Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution Venkatesan S, Angelova M, Puttick C et al. Cancer Discovery (2021) 11(7) 2456-2473

RTEL1 Regulates G4/R-Loops to Avert Replication-Transcription Collisions Kotsantis P, Segura-Bayona S, Margalef P et al. Cell Reports (2020) 33(7)

Spotlight on the Replisome: Aetiology of DNA Replication-Associated Genetic Diseases Bellelli R, Boulton SJ Trends in Genetics (2020) (1)

Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication Bellelli R, Youds J, Borel V et al. Cell Reports (2020) 31(7)

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency Logan CV, Murray JE, Parry DA et al. American Journal of Human Genetics (2018) 103(7) 1038-1044

POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication Bellelli R, Belan O, Pye VE et al. Molecular Cell (2018) 72(7) 112-126.e5

Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis Bellelli R, Borel V, Logan C et al. Molecular Cell (2018) 70(7) 707-721.e7

Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe Margalef P, Kotsantis P, Borel V et al. Cell (2018) 172(7) 439-453.e14

Team

• Ms Bethany Rebekah Hill

Biography

I studied medicine and surgery at the University of Naples, Federico II (Italy), where I graduated with honours in 2008 with a thesis on the molecular pathology of thyroid cancer.

After entering the Italian medical board, I joined the PhD program in Molecular Oncology and Endocrinology at the same faculty, and obtained my PhD in 2012. My work has been focused on the role of the NCOA4 gene, which is rearranged in human cancer, in the control of DNA replication and iron metabolism (Bellelli et al., Mol. Cell, 2014; Bellelli et al., Cell Reports, 2016).

In 2015, for my post-doctoral studies, I moved to the laboratory of Prof. Simon Boulton at the Francis Crick Institute in London, where I studied the mechanisms that control genome stability during DNA replication.

Using a combination of approaches, ranging from mouse genetics to biochemistry and cell biology, I discovered an essential double function for the POLE3-POLE4 components of DNA Polymerase Epsilon in the control of initiation of DNA replication and replication-coupled nucleosome assembly, with important implications for both human genetic disease and cancer (Bellelli et al., Mol Cell 2018a; Bellelli et al., Mol Cell 2018b).

In February 2020, I joined the Barts Cancer Institute as a Group Leader. My lab will study the mechanisms that control genome and epigenome stability at the replication fork and how they are dysregulated in cancer.