More than one hundred key genes linked to DNA damage have been uncovered through systematic screening of nearly 1,000 genetically modified mouse lines, in a new study published today (14 February) in Nature.
The work provides insights into cancer progression and neurodegenerative diseases as well as a potential therapeutic avenue in the form of a protein inhibitor.
In this new study, researchers from the Wellcome Sanger Institute, and their collaborators at the UK Dementia Research Institute at the University of Cambridge, set out to better understand the biology of cellular health and identify genes key to maintaining genome stability.
Using a set of genetically modified mouse lines, the team identified 145 genes that play key roles in either increasing or decreasing the formation of abnormal micronuclei structures. These structures indicate genomic instability and DNA damage, and are common hallmarks of ageing and diseases.
The most dramatic increases in genomic instability were seen when the researchers knocked out the gene DSCC1, increasing abnormal micronuclei formation five-fold. Mice lacking this gene mirrored characteristics akin to human patients with cohesinopathy disorders, further emphasising the relevance of this research to human health.
Using CRISPR screening, researchers showed this effect triggered by DSCC1 loss could be partially reversed through inhibiting protein SIRT1. This offers a highly promising avenue for the development of new therapies.
The findings help shed light on genetic factors influencing the health of human genomes over a lifespan and disease development.
Professor Gabriel Balmus, senior author of the study at the UK Dementia Research Institute at the University of Cambridge, formerly at the Wellcome Sanger Institute, said: “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.”
Dr David Adams, first author of the study at the Wellcome Sanger Institute, said: “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.”
Notes to Editors:
Various sources of damage to the genome can include radiation, chemical exposure, and errors during DNA replication or repair processes.
Micronuclei are small abnormal structures, often referred to as "mutation factories", containing misplaced genetic material, that should otherwise be in the cell nucleus. Their presence signifies an increased risk of diseases like cancer and developmental disorders.
Cohesinopathy disorders are a group of genetic conditions resulting from dysfunctional cohesin proteins, essential for proper chromosome organisation and segregation during cell division. This can lead to a spectrum of developmental abnormalities, intellectual disability, distinctive facial features and growth retardation.
When the SIRT1 protein was suppressed, DNA damage reduced and they could rescue the negative effects of DSCC1 loss associated with cohesion disruption. This action was via restoring chemical levels of a protein called SMC3.
(Newswise/VV)
