Mechanism of nucleosome assembly during DNA replication

Project Information

EpiRep

Grant agreement ID: 851564

DOI

10.3030/851564

Project closed

EC signature date 9 September 2019

Start date 1 December 2019

End date 30 November 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands

Periodic Reporting for period 4 - EpiRep (Mechanism of nucleosome assembly during DNA replication)

Reporting period: 2024-06-01 to 2024-11-30

Summary of the context and overall objectives of the project

Cell division maintains life for all living organisms. Complex molecular mechanisms are in place to ensure accurate cell division. A critical step in cell division occurs when the genome is replicated. This process copies the genetic and epigenetic information that will be inherited by the daughter cells. Often these mechanisms are deregulated in cancer, and they greatly affect tissue homeostasis and development. We study these processes using a combination of biochemical and cellular approaches, to understand what are the molecular mechanism and their linked function. These study help us to find way to target these mechanisms and understand their consequences for the life of a cell. Our work can provide new ways to treat cancer and other diseases.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our work has shows that the chromatin and DNA replication machineries closely interact. In particular we found that the chromatin machinery can directly affect the speed of DNA replication. This close link between genetic and epigenetic mechanisms reveals that these two aspects are tightly connected, and therefore they can not be disentangled at replication forks. We have on the one side further delved into how these two processes are linked using in vitro biochemistry. On the other side, using cells, we have also demonstrated that this connection is closely coupled to cell cycle regulatory signals, which perturb cell proliferation in a multi-layered fashion. These findings open the door to now a plethora of new discoveries on these connections, their molecular basis, and their potential role in disease. We also established a variety of new methods that can be used to study other aspects of DNA and chromatin replication.
I have presented our work at several conferences, well before their publication, which enable timely dissemination within the field and research progress. In the past years, we have also established collaborations with other groups to use our expertise to tackle other relevant questions in chromatin bioclogy and replication.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We have developed methods that enable quantitative measurements on a vital process in biology. Our biochemical reconstitutions use a very high level of complexity, combining the activity of over 60 different proteins as part of the yeast replisome, acting on long chromatinized DNA molecules. This complexity is unique and beyond the state-of-the-art. We successfully established also unique cellular tools to study chromatin assembly during DNA replication in human cells. The synergy between our sophisticated biochemistry and cell-based tools allow us now to study chromatin replication across scale from molecules to cells, giving us a unique niche in the field. Our work is enabling a better understanding of chromatin dynamics during DNA replication. While we understand how DNA is replicated, how chromatin is copied remains unclear, and we are significantly contributing to making discoveries in this direction.

graphical-abstract-final.png