A new study by researchers from the Wellcome Sanger Institute and their collaborators at the UK Dementia Research Institute at the University of Cambridge sought to determine the biology of cellular health and identify genes keys to maintaining genome stability. The researchers uncovered 145 genes through systematic screening of nearly 1,000 genetically modified mouse lines, and possible strategies to curb progression of human genomic disorders.
The findings are published in Nature in an article titled, “Genetic determinants of micronucleus formation in vivo.”
“Genomic instability arising from defective responses to DNA damage or mitotic chromosomal imbalances can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN),” the researchers wrote. “Although MN are a hallmark of aging and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease.”
Using a set of genetically modified mouse lines, the researchers discovered 145 genes that play key roles in either increasing or decreasing the formation of abnormal micronuclei structures.
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.
Using CRISPR screening, researchers showed this effect triggered by DSCC1 loss could be partially reversed through inhibiting protein SIRT14.
Gabriel Balmus, PhD, 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.”
David Adams, PhD, 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, 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.”
