Camilla Björkegren

Cellular function and organism development require a multitude of factors that transcribe, duplicate, repair, and segregate chromosomal DNA. These processes depend on the three-dimensional (3D) organization of chromosomes and are influenced by changes in the helical structure of DNA, so called supercoiling. Contrary to the expectations in the field, we have revealed that DNA supercoiling controls chromosome 3D organization via a family of chromosome-folding machines called SMC protein complexes (e.g., Nature 2011

Cell Reports 2015, Science Adv. 2022, Nature 2023

Mol. Cell 2024). This opens a new fundamental area of chromosome research which we will explore during the coming eight years. The specific aims are to determine:The molecular details of the DNA supercoiling / SMC complex / chromosome organization interplay.The impact of this interplay on a) early development and b) inhibition of virus duplication. The project builds upon an international research environment that unite a wide variety of expertise, and methods such as single molecule analysis, high resolution microscopy, bioinformatics, in vivo models, and a unique marker for chromosomal supercoiling we recently discovered. Given the fundamental nature of DNA supercoiling, and the vital roles of SMC complexes and chromosome 3D organisation, these investigations will close a significant gap in our understanding of chromosome dynamics and function.

Cellular function requires a multitude of proteins and co-factors that allow chromosomal DNA to be properly transcribed, duplicated, repaired, and segregated. In turn, these processes depend on the three-dimensional (3D) folding of chromosomes, and are influenced by changes in the helical structure of DNA, so-called supercoiling. We and others have suggested that supercoiling is functionally connected to chromosome 3D organization, but direct evidence has been lacking. Collectively, our investigations now show that a family of chromosome-folding machines, called Structural Maintenance of Chromosome protein complexes, indeed link supercoiling to chromosome 3D organization (e.g., Nature 2011, Cell Rep. 2015, Science Adv. 2022, Nature 2023). The purpose of the presented project is to determine how this mostly unknown interplay contributes to chromosome function. The specific aims are to:1)  Establish the molecular mechanisms of the DNA supercoiling-chromosome folding interplay.2) Determine how the supercoiling-folding interplay influence transcription and early development.This will be achieved by combining a variety of methods such as high-resolution micro-C analysis, single molecule analysis, high resolution microscopy, various in vivo models, and a unique marker for DNA supercoiling that we recently discovered. This will unravel new fundamental principles of chromosome organization and provide insights into the cellular defence against disease-related chromosomal aberrations.

Our body is made up of cells, and the information needed for normal growth is stored in the cell's chromosomes, which make up our genetic makeup. These consist of two strands of DNA, organized into a double helix. The helix is an excellent structure for storing the code of life, but also an obstacle as the strands must be pryed apart when the cell reads the vital information. When this happens, the structure of the helix changes, and much is known about the cellular mechanisms that correct this problem. Our new results indicate that the structural change can also have a positive effect by controlling chromosome folding, which in turn counteracts chromosome changes. Through analysis in cellular model systems and of isolated proteins, our project investigates how a cell is able to take care of structural changes in the DNA helix and fold its chromosomes correctly. If this does not happen, it will hinder other processes that protect against the accumulation of cells with the wrong number, broken or mutated chromosomes. As such chromosomal changes are linked to tumor development, it is important to understand these processes in detail. Our research maps these details. The main goal of the project is to increase the understanding of what happens when a cancer cell is formed by identifying molecular mechanisms that prevent chromosomal changes. The project will also reveal new details about a family of enzymes that are targets for already established cancer treatment. By producing this knowledge at the molecular level, the project can open up the development of new and improved cancer treatment.