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DNA Replication: From Physiology to Replication Stress in Human Cancer

Objectif

Replication of the genome is of critical importance for cell proliferation and organismal development. To ensure accurate and complete replication of their genome, eukaryotes have hundreds to thousands of replication origins. In budding yeast, the genomic positions of all the origins are known, as is the order in which they fire. In contrast, in human cells, the mapping of origins is controversial and origin firing may be stochastic and plastic. Furthermore, while normal cells replicate their genomes with high fidelity; in cancer cells, the presence of activated oncogenes leads to collapse of DNA replication forks (DNA replication stress), DNA damage and genomic instability.

My laboratory has recently elucidated key differences in DNA replication after oncogene induction. We mapped replication origins on the human genome and found that, in addition to the origins present before oncogene induction, a new class of “oncogene-induced” origins was observed upon activation of the CCNE1 (Cyclin E) or MYC (c-Myc) genes. Only forks from the oncogene-induced origins were prone to collapse, leading to the genomic instability patterns observed in the common human cancers.

In this proposal, we aim to map with high precision the human replication origins, determine if their firing is stochastic or deterministic and identify sequence motifs that are important for origin firing (Aim 1). We further aim to explore how transcription in the G1 phase of the cell cycle regulates origin firing (Aim 2). This endeavour is motivated by our observation that transcription in G1 inactivates intragenic origins. Finally, we aim to understand how transcription, replication and repair are coordinated to avoid DNA replication stress in normal cells (Aim 3).

The proposed experiments will help us understand how normal cells replicate their genome with high fidelity and how oncogenes interfere with this process.
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Institution d’accueil

UNIVERSITE DE GENEVE

Adresse

Rue Du General Dufour 24
1211 Geneve

Suisse

Type d’activité

Higher or Secondary Education Establishments

Contribution de l’UE

€ 2 231 378

Bénéficiaires (1)

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Trier par contribution de l’UE

Tout développer

UNIVERSITE DE GENEVE

Suisse

Contribution de l’UE

€ 2 231 378

Informations projet

N° de convention de subvention: 788681

État

Projet en cours

  • Date de début

    1 Octobre 2018

  • Date de fin

    30 Septembre 2023

Financé au titre de:

H2020-EU.1.1.

  • Budget total:

    € 2 231 378

  • Contribution de l’UE

    € 2 231 378

Institution d'accueil:

UNIVERSITE DE GENEVE

Suisse