A hair-trigger for cells fighting infection

To fight infections cells in the immune system play a dangerous game with their own genes. Damaging genes allows B cells to make antibodies that are specifically equipped to target to specific causes of illness, but damaging genes also puts them at risk of becoming cancerous. A new study led by scientists at the Babraham Institute in Cambridge, UK identifies Tia1 as a hair-trigger protein that stop our body’s defences from turning against us.

All cells experience DNA damage but it’s usually minor and can be repaired. The latest research, published in the journal Nature Communications, highlights that standard repair processes are too slow for B cells, where intentional DNA damage is more severe. The results show that B cells plan ahead, priming the DNA repair process early, so when they intentionally damage their own DNA it can be fixed before it causes lasting harm.

As the paper’s first author, Dr Manuel Díaz-Muñoz said: “B cells walk a fine line, some DNA damage is needed for them to make effective antibodies to fight infections, but too much and they become harmful. It’s a tough situation to manage biochemically. Tia1 controls the production of a number of proteins that help cells respond to damaged DNA. Tia1 allows a rapid response from B cells so they can repair DNA damage at a moment’s notice.”

Each illness requires a specific antibody to defeat it. By damaging and repairing the genetic instructions that make antibodies, each B cell produces a unique antibody type and the most effective ones are then used to fight disease. This causes extensive damage to the DNA inside B cells and must be rapidly repaired or genetic mistakes may weaken the immune system or even cause cancer.

Scientists believed that B cells only turn on DNA repair genes when they are needed to repair damage. Yet, these new results completely change this view. These genes are constantly active, but cells only use the information in these genes to make proteins when there is a lot of DNA damage. B cells prepare templates for the proteins but don’t go on to make the proteins themselves.

Tia1 is the protein that enables B cells to stop making DNA repair proteins part way through. When DNA damage is low, Tia1 gathers together the protein templates, called mRNAs, for lots of different DNA repair proteins. When DNA damage increases Tia1 can quickly release all the mRNAs it collected and the cell uses them to make lots of the proteins it needs to fix its genes.

Head of the Lymphocyte Signalling Programme at the Babraham Institute and senior scientist on the paper, Dr Martin Turner, said: “Remarkably, our data suggest that regulation of mRNAs by Tia1 rather than protein destruction controls DNA repair in activated B cells. This is an attractive and little explored mechanism that we are now starting to understand. Controlling protein production in this way is important in other healthy and diseased cells and it will be interesting to see if a similar system exists in other places.”

Notes to Editors:

Publication Reference
Díaz-Muñoz, MD., Yu Kiselev, V., Le Novère, N., Curk, T., Ule, J., Turner, M., (2017) 'Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells'. Nat Comms 8. http://dx.doi.org/10.1038/s41467-017-00454-2

Research Funding
This research was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust.

Press Contact
Dr Jonathan Lawson, Babraham Institute Communications Manager

Image Credit
Credit: Dr Manuel Díaz-Muñoz
Microscopy image showing collections of mRNA molecules, called RNA granules (green), inside B cells that are altering their genes to produce antibodies. DNA is shown in blue.

Affiliated Authors (in author order):
Manuel Díaz-Muñoz, Lymphocyte Signalling & Development Programme, Babraham Institute
Vladimir Yu Kiselev, Signalling Programme, Babraham Institute
Martin Turner, Group Leader, Lymphocyte Signalling & Development Programme, Babraham Institute

Animal Statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. Animals are only used in Babraham Institute research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the Babraham Research Campus for research purposes.

The use of animals in this study was performed with approval from the Babraham Institute’s Animal Ethics Board AWERB and in accordance with the UK Home Office legislation. The study used B cells collected from the spleens of 8-12 week old C57BL/6 mice housed at the Institute following established protocols that guarantee animal health and wellbeing. The minimum number of mice were used, whilst ensuring statistically meaningful data, in accordance with ARRIVE animal use guidelines.

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About the Babraham Institute:
The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.