Sheffield Institute for Nucleic Acids

Genome Stability

Every day, our DNA is damaged from many different sources such as free radicals produced within the cell as it makes energy, UV exposure from sunlight, and from damaging chemicals in cigarette smoke and alcohol. If not accurately repaired, such damage can give rise to mutations and genomic instability; an inability to faithfully pass on genetic information to progeny, which can lead to many different human diseases and ageing processes.

For example; genome instability is a defined hallmark of human cancers and can impact on our ability to effective treat the disease. Given this, our cells have developed many different mechanisms and process that function every day to maintain a stable genome.

A comet assay which measures the amount of DNA damage in a cell. The dots with tails which look like comets correspond to cells with extensive DNA damage
Visualisation of a DNA replication fork.

Work within SInFoNiA focuses on furthering our understanding of how human cells maintain a stable genome throughout development and ageing, and how these process can go wrong in human diseases such as cancer. Collaborative research between molecular and cellular biologists, biochemists, medicinal and structural chemists and clinicians across three Faculties and several Departments ensures that we maximise our fundamental biological findings into translational impact.

Our research into genome stability can be divided into three major areas of focus and expertise:

Research carried out within the Institute and elsewhere in the world has revealed that all of these genome stability processes are highly interconnected and co-regulated. Through the collaborative approach taken by our Institute experts in these areas, as well as with colleagues both in the UK and across the world, we are making important fundamental discoveries in this area, and taking such findings from our research laboratories through to pre-clinical and clinical studies.

DNA replication and segregation

Research within SInFoNiA is being carried that aims to understand how human cells accurately copy their genome under normal growth conditions, and how they respond to lesions that impede on-going DNA synthesis. A heightened replicative capacity is a hallmark of human cancers due to their dysregulated growth, and researchers within SInFoNiA are trying to find news ways to exploit this to improve the treatment of human cancers. These processes are also vital to a range of viruses that infect humans, livestock and crops. As such, researchers within SInFoNiA are studying these processes within specific viruses in order to reveal new treatment strategies against such infections. Several groups are also interested in how human cells accurately segregate their chromosomes during mitosis and/or meiosis, and how these processes can become dysregulated in human cancers.

Cellular responses to DNA damage

Every day, thousands of DNA damaging events occur within a cell which must be accurately repaired in order to maintain a stable genome. A key part of this process is how a cell can rapidly detect such damage and activate the appropriate cellular responses to facilitate accurate repair mechanisms. If the damage is too much for a cell to deal with, then alternative failsafe mechanisms trigger, leading to the destruction of the cell to prevent potentially pro-mutagenic lesions being passed on to progeny. These DNA repair and failsafe processes are often dysregulated in human cancers, and researchers within SInFoNiA are trying to understand how this occurs, and how it may offer a means to specifically kill cancer cells to improve current and future therapeutic regimes for cancer patients. These repair processes are also important during development and the attrition of genome integrity is a cause of cellular and organismal ageing. As, SInFoNiA researchers are also studying various aspects of these mechanisms in development and ageing.

RNA processing and export

Before making functional proteins, all genes in our DNA must be copied into a special messenger molecule called mRNA that travels from the nucleus (where the DNA is stored) into the cytoplasm (where proteins are made). This process is called mRNA processing and export, and like DNA replication and chromosome segregation, this must be carried out in an accurate and efficient manner to prevent genomic instability. Researchers within the Institute are determining how cells maintain and regulate the vital cellular processes involving mRNA processing and export, and how they go wrong in human diseases such as cancer and motor neuron disease.