DNA Replication: From Physiology to Replication Stress in Human Cancer
ERC Advanced Investigator Grant
October 2018-September 2023
Proliferation of cells requires that the genome becomes duplicated, before each cell division. This ensures that the daughter cells have the same genomic information as the mother cell. Duplication of the genome is performed by a process called DNA replication. The genome contains specific sites, where DNA replication begins. These sites are called origins of DNA replication. In this project we aim to define precisely where the DNA replication origins are located in the genome and the specific DNA sequences that are needed for DNA replication to begin at a specific site. We also want understand how DNA replication is coordinated with gene transcription. Transcription is needed to generate RNA and eventually for protein synthesis. The DNA replication machinery and the transcription machinery use the same DNA template. We intend to understand how collisions between the DNA replication and transcription machineries are avoided. These studies are relevant for understanding cancer development and progression. In cancer, there are new DNA replication origins that fire, which origins do not fire in normal cells. Moreover, in cancer cells, there are collisions between the DNA replication and transcription machineries that lead to DNA damage. Therefore, this research project may provide insights that help the development of new cancer therapies.
The proposed project has 3 Aims.
Aim 1. Determine whether origin firing in human cells is stochastic or deterministic; map the origin firing sites at high resolution; and identify functionally important origin motifs.
Aim 2. Determine the mechanisms by which transcription in G1 suppresses firing of intragenic origins.
Aim 3. Determine why forks from intergenic origins do not collapse when replicating highly transcribed genes.
Open PhD Student and Postdoctoral Positions
PhD Student and Postdoctoral positions are available to work on this project. Interested candidates can send their CV, unofficial grades from their Bachelor studies and short motivation letter to Thanos Halazonetis