Loss of Dscc1 leads to early developmental defects and increased genomic instability. AHeart and liver abnormalities Dscc1−/− E14.5 mouse embryos. The axial section (left; dorsal up) and sagittal resections (right; ventral up) were obtained by high-resolution episcopic microscopy (HREM) analysis of a Dscc1-mutant (bottom) and a WT embryo (top). Bottom left, a ventricular septal defect (VSD) in a Dscc1−/− embryo. Bottom right, abnormal liver texture, specifically a cyst (white asterisk) and abnormally enlarged hepatic sinusoids associated with a reduced number of hepatocytes (black asterisk) in the liver lobe of a Dscc1−/− embryo. di, diaphragm; e, esophagus; li, liver; LV, left ventricle; PR, right atrial appendage; RV, right ventricle; VS, ventricular septum. Scale bars, 1 mm. Three embryos per genotype were analyzed. b, Growth curves of primary mouse embryonic fibroblasts (MEFs) over 5 days in culture. Two independent WTs and two independents Dscc1−/− MEF lines derived from littermate embryos are shown. not= 3 independent repetitions each. Data are mean ± standard deviation. Statistical analysis was performed using the two-sided Student’s test. t-tests comparing the values of the area under the curve (AUC). vsFlow cytometry analysis of MEFs, showing increased genomic instability, as measured by the presence of γH2AX-positive cells, an indicator of the presence of DNA damage. not = 3 biological replicates each. Data are mean ± standard deviation. Statistical analysis was performed using the two-sided Student’s test. t-tests. d, Representative images of chromosomal abnormalities observed in primary MEFs of the indicated genotypes at passage 3 (left). On the right, the percentage of abnormalities due to chromosome spread comparing WT with Dscc1−/− MEF. not = 3 biological replicates measuring not= 10 metaphases per genotype in each experiment. Statistical analysis was performed using two-way analysis of variance. Scale bars, 5 µm. eKaplan-Meyer analysis of DSCC−/− mice, showing that they exhibit reduced latency of tumor formation. Information on age and gender is provided in the source data. not= 20 (WT) and not= 9 (Dscc1−/−) mouse. Statistical analysis was performed using log-rank tests (Mantel–Cox). Credit: Nature(2024). DOI: 10.1038/s41586-023-07009-0
More than a hundred key genes linked to DNA damage were discovered through systematic screening of nearly 1,000 genetically modified mouse lines in a new study published in Nature.
The work provides insight into the progression of cancer and neurodegenerative diseases as well as a potential therapeutic avenue in the form of a protein inhibitor.
The genome contains all the genes and genetic material contained in an organism’s cells. When the genome is stable, cells can replicate and divide precisely, passing on the correct genetic information to the next generation of cells. Despite their importance, little is known about the genetic factors that govern genome stability, protection, repair, and prevention of DNA damage.
In this new study, researchers from the Wellcome Sanger Institute and their collaborators from the UK Dementia Research Institute at the University of Cambridge set out to better understand the biology of cellular health and identify genes essential for maintaining genome stability .
Using a set of genetically engineered mouse lines, the team identified 145 genes playing key roles in increasing or decreasing the formation of abnormal micronucleus structures. These structures indicate genomic instability and DNA damage, and are common features of aging and disease.
The most dramatic increases in genomic instability were seen when researchers knocked out the DSCC1 gene, increasing abnormal micronucleus formation fivefold. Mice lacking this gene reflected characteristics similar to those of human patients with cohesinopathy disorders, highlighting the relevance of this research to human health.
Using CRISPR screening, the researchers showed that this effect triggered by loss of DSCC1 could be partially reversed by inhibiting the SIRT1 protein. This offers a very promising avenue for the development of new therapies.
The findings help shed light on the genetic factors influencing the health of the human genome over the lifespan and the development of disease.
Professor Gabriel Balmus, lead author of the study at the UK Dementia Research Institute at the University of Cambridge, formerly at the Wellcome Sanger Institute, said: “Continuing to explore genomic instability is essential for developing treatments. tailored solutions that address root genetic causes, with the goal of improving outcomes and overall quality of life for individuals in a variety of conditions.
“Our study highlights the potential of SIRT inhibitors as a therapeutic avenue for cohesinopathies and other genomic disorders. It suggests that early intervention, specifically targeting SIRT1, could help mitigate biological changes linked to genomic instability before ‘They are not progressing.’
Dr David Adams, first author of the study at the Wellcome Sanger Institute, said: “Genomic stability is essential for cell health, influencing a spectrum of diseases from cancer to neurodegeneration, but it is a relatively under-explored area of research. “.
“This work, in progress for 15 years, illustrates what can be learned from large-scale unbiased genetic screening. The 145 genes identified, particularly those linked to human diseases, offer promising targets for the development of new therapies for diseases caused by genome instability such as cancer and neurodevelopmental disorders.
More information:
David Adams, Genetic determinants of micronucleus formation in vivo, Nature(2024). DOI: 10.1038/s41586-023-07009-0. www.nature.com/articles/s41586-023-07009-0
Provided by the Wellcome Trust Sanger Institute
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