New Understanding of DNA Damage and Disease Risk

Researchers identified 145 genes that are essential for the health of the genome and potential treatments for human genomic disorders.

New Understanding of DNA Damage and Disease Risk

Image Credit: Fengtang Yang / Wellcome Sanger Institute

In a new study published in Nature, systematic screening of nearly 1,000 genetically modified mouse lines revealed more than one hundred key genes associated with DNA damage.

The research offers new perspectives on the course of neurodegenerative illnesses and cancer, as well as a possible treatment option in the form of protein inhibitors.

All of the genes and genetic material found in an organism’s cells are contained in its genome. Cells can reproduce and divide correctly when the genome is stable, transferring accurate genetic information to the following generation of cells. The genetic factors controlling genome stability, protection, repair, and DNA damage prevention are poorly understood despite their importance.

To better understand the biology of cellular health and identify genes essential to preserving genome stability, researchers from the Wellcome Sanger Institute and their partners at the UK Dementia Research Institute at the University of Cambridge set out to conduct this new study.

The scientists discovered 145 genes that are crucial in either promoting or inhibiting the development of aberrant micronuclei structures using a collection of genetically altered mouse lines. These structures are typical indicators of aging and disease since they show genomic instability and DNA damage.

The researchers observed that when they eliminated the gene DSCC1, the formation of aberrant micronuclei increased five-fold, resulting in the most significant increases in genomic instability. The relevance of this research to human health is further highlighted by the fact that mice lacking this gene exhibited characteristics similar to those of human patients with cohesinopathy disorders.

Researchers used CRISPR screening to demonstrate that protein SIRT14 inhibition could partially reverse the effect caused by DSCC1 loss. This presents an extremely promising path for the creation of novel treatments.

The results provide insight into the role that genetic factors play in both the development of diseases and the lifespan health of human genomes.

Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes, with the goal of improving outcomes and the overall quality of life for individuals across various conditions. Our study underscores the potential of SIRT inhibitors as a therapeutic pathway for cohesinopathies and other genomic disorders. It suggests that early intervention, specifically targeting SIRT1, could help mitigate the biological changes linked to genomic instability before they progress.”

Gabriel Balmus, Study Senior Author and Professor, UK Dementia Research Institute, University of Cambridge

Balmus was formerly at the Wellcome Sanger Institute.

Genomic stability is central to the health of cells, influencing a spectrum of diseases from cancer to neurodegeneration, yet this has been a relatively underexplored area of research. This work, of 15 years in the making, exemplifies what can be learned from large-scale, unbiased genetic screening. The 145 identified genes, especially those tied to human disease, offer promising targets for developing new therapies for genome instability-driven diseases like cancer and neurodevelopmental disorders.”

Dr. David Adams, Study First Author, Wellcome Sanger Institute

Source:
Journal reference:

Adams, J. D., et.al. (2024) Genetic determinants of micronucleus formation in vivo. Nature. doi.org/10.1038/s41586-023-07009-0.

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