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De Piccoli Lab

Giacomo de Piccoli

Research Summary

The accurate duplication of the genome is essential for the survival of all living cells, and acts as a critical barrier to the development of cancer in humans. Failure to complete DNA replication leads to chromosome breaks, translocation, loss of heterozygosity or cell death. Our lab aims to understand one of the most important pathways that allow cells to survive defects in DNA replication, known as the S-phase checkpoint.

Chromosome duplication starts with the assembly on the DNA of the replication machinery, referred to as the replisome. This is composed of a heteromeric DNA helicase called Cdc45-MCM-GINS, three different DNA polymerases, and many regulatory factors (in figure below).

Defects in DNA replication cause the accumulation of single-stranded DNA at replication forks, which triggers a highly conserved signalling cascade that is known as the S-phase checkpoint. In human cells this involves activation of the ATR protein kinase, which drives activation of the effector kinase called Chk1.

 Replisome 2

Studies of the budding yeast functional orthologues of mammalian ATR and Chk1, known as Mec1 and Rad53, have shown that they play many roles in response to DNA replication stress, including the regulation of cell cycle progression, gene expression, firing of origins of replication, DNA recombination and repair. However, the mechanisms underlying the S-phase checkpoint response at forks are still poorly understood.

My work (De Piccoli et al, 2012) has shown that replisome stability is independent of checkpoint kinases, and our focus over the next few years will be to study how the checkpoint pathway regulates aspects of replisome function. We have identified novel post-translational modifications of the replisome that are controlled by the S-phase checkpoint pathway, and we will determine whether these control the recruitment of regulatory factors to the replisome, or else directly modulate the activity of key replisome components.

We are always looking for bright and motivated PhD students to join the lab. If you are interested, please contact me by email at G dot de-Piccoli at warwick dot ac dot uk.

Warwick University Profile | Email

We are always looking for talented and enthusiastic people who would like to join as research fellows. Please click here to view our latest job opportunites

Recent Publications

Maric, M., Maculins, T., De Piccoli, G., Labib, K. (2014) Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication. Science Oct 24;346(6208): 1253596. doi: 10.1126/science.1253596 PubMed

Sengupta, S., Van Deursen, F., De Piccoli, G., Labib, K. (2013) Dpb2 Integrates the Leading-Strand DNA Polymerase into the Eukaryotic Replisome. Curr. Biol. PubMed

Foltman, M., Evrin, C., De Piccoli, G., Jones, R.C., Edmondson, R.D., Katou, Y., Nakato, R., Shirahige, K., Labib, K. (2013) Eukaryotic replisome components cooperate to process histones during chromosome replication. Cell Rep. 2013 Mar 28;3(3):892-904 PubMed

Kilkenny, M.L., De Piccoli, G., Perera, R.L., Labib, K., Pellegrini, L. (2012) A conserved motif in the C-terminal tail of DNA polymerase a tethers primase to the eukaryotic replisome. J Biol Chem. 2012 May 22 PubMed

Van Deursen, F., Sengupta, S., De Piccoli, G., Sanchez-Diaz, A., Labib, K. (2012) Mcm10 associates with the loaded DNA helicase at replication origins and defines a novel step in its activation. EMBO J. 2012 Mar 20;31(9):2195-206 PubMed

De Piccoli, G., Katou, Y., Itoh, T., Nakato, R., Shirahige, K., Labib, K. (2012) Replisome stability at defective DNA replication forks is independent of S phase checkpoint kinases. Mol Cell. 2012 Mar 9;45(5):696-704. PubMed

Bermúdez-López, M., Ceschia, A., de Piccoli, G., Colomina, N., Pasero, P., Aragón, L., Torres-Rosell, J. (2010) The Smc5/6 complex is required for dissolution of DNA-mediated sister chromatid linkages. Nucleic Acids Res. 2010 Oct 1;38(19):6502-12. PubMed

Lab Members and Projects

 Alicja Winczura

Alicja Winczura | Research Fellow
I work on the regulation of DNA replication in response to DNA damage.


Edward Miller | Research Assistant
My research will investigate how modifications of components of the replisome modulate its activity.


Rowin Appanah | PhD Student
I work on novel regulators of the replication process.


 Nick Sillett | PhD Student

My research focuses on how replisome composition changes during replication stress and how this affects its progression.