Press Release

01.03.2021

Dr. Till Bartke receives DFG funding to unravel the mysteries of replication origins

Replication is the fundamental process that ensures that every cell within an organism contains the same hereditary information. Each cell has many origins of replication (ORIs), but not all of them are active. Moreover, cells, even if they are from the same cell type, can differ in their active ORIs. Thus, there are still many open questions about how replication starts. Dr. Till Bartke receives more than 490.000 € to study how a cell decides which ORIs to activate and how the ORI activation is coordinated.

@Till Bartke; adapted from Fragkos et al. (2015), Nat Rev Mol Cell Bio

The grown-up human body consists of trillions of cells and it is one of the most fascinating aspects of life that they all have one cell – the fertilized egg (zygote) – as common ancestor. Around 30 hours after fertilization the zygote divides to become a 2-cell-stage embryo, and through multiple rounds of cell division and differentiation steps, the zygote gives rise to more than 200 different body cell types and generates a completely new human-being. After ‘completion’, some cells continuously divide to construct and repair the organism, while others stop growing. In one lifetime of a human, around 10 quadrillion cell divisions will take place.

Each of our body cells safely stores our hereditary information within the DNA inside the nucleus. Because they all have the same zygote as ancestor, each cell in an organism contains the same DNA, which has been passed on from the ‘mother’ to the ‘daughter’ cells. However, in order to pass it on, the DNA has to be duplicated before the cell divides. The process responsible for making an accurate copy of the DNA is called replication.

The DNA is composed of two strands of nucleotide bases that are connected through complementary base pairing*, forming a double helix - similar to a zipper. During replication, the DNA gets unzipped and the now single-stranded DNA serves as template for building the new second stand. Thus, following replication, the cell contains double the amount of DNA, which will be evenly distributed to the mother and the daughter cell during cell division.

In humans, the DNA within a cell is around 2 m long, which is extremely large compared to the size of a cell (100 µM on average) or the nucleus (10 µm). If replication were to start from only one starting point it would take over a month to replicate all of the DNA. Luckily, in contrast to a normal ‘zipper’, the DNA has more than one starting point for unzipping – approximately 60,000 so called origins of replication (ORIs). Therefore, by using many of these ORIs it takes the cell only a few hours to duplicate its full DNA content.

Interestingly, not all ORIs are active in a cell at the same time. Some are activated earlier than others and some will never be activated. It is even more puzzling that two cells from the same cell type activate different ORIs. It has been suggested that the way the DNA is organized** within the nucleus plays an important role in selecting ORIs, and that ORIs that are in close proximity to each other are activated together. However, how a cell decides which ORI should be activated and how it coordinates their activation is still unclear.

During his time at the Gurdon Institute in Cambridge, Dr. Till Bartke, now the Deputy Director of the Institute of Functional Epigenetics at the Helmholtz Zentrum München, has come across the protein LRWD1, which could be the missing piece in the puzzle. “We identified LRWD1 as a subunit of the origin recognition complex (ORC), which is required for DNA replication to start”, explained Dr. Bartke. “Interestingly, in our recent work we found that LRWD1 is recruited to genomic sites where a factor that is important for maintaining the three-dimensional organization of the genome also localizes. LRWD1 might therefore play a role in bringing the ORIs, which should be activated, into close proximity.” (See illustration) To follow this hot trace, the DFG awarded Dr. Till Bartke and his team with a grant of 492.850 € (Award Number BA 6383/4-1), which includes funding for two PhD positions (Job ad: bit.ly/3bOk9nx).

The project will approach the research question from different angles and use genome engineering and complementary genomic and microscopic techniques to analyze the role of LRWD1 in coordinating ORI activation. “I am delighted to be given this opportunity to follow up on our findings and to investigate whether LRWD1 links chromatin folding and DNA replication. It is clear that chromatin organization and DNA replication are deeply intertwined, but how this could work at the molecular level is essentially unknown. It will be exciting to see whether LRWD1 plays a role in this and what this role might be.” 

Further information:

* The DNA double helix is a molecule consisting of two polynucleotide strands. The monomeric units of each strand are the nucleotide bases Guanine, Adenosine, Thymine and Cytosine. The two polynucleotide strands are held together by hydrogen bonds between the nucleotides. Guanine always forms hydrogen bonds with Cytosine and Adenosine with Thymine.

** From yeast to human, the three-dimensional (3D) genome organization is conserved with accessible DNA in the center of the nucleus and less accessible DNA at the periphery. Accessible DNA is replicated earlier than less accessible DNA.

Bartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T. (2010). Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell.