145 genes have been identified as key to maintaining genome stability, protection, repair, and preventing DNA damage.
The study, published in Nature, found key genes linked to DNA damage and human disease through systematically screening of almost 1000 genetically modified mouse lines. The findings could help to provide further insight into cancers, ageing and inflammatory diseases.
'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' said Professor Gabriel Balmus, senior author of the study, from the University of Cambridge.
Through their analysis of mutant mouse lines, researchers from the Wellcome Sanger Institute, and their collaborators at the UK Dementia Research Institute at the University of Cambridge, revealed that the increase or decrease of 145 genes affected the formation of a chromosome fragment called micronuclei, which are indicators of genomic instability and DNA damage.
In particular, the scientists noted that when inactivating a particular gene, DSCC1, abnormal micronuclei formation increased five-fold. Without this gene, mice had characteristics similar to patients with cohesinopathy disorders, which cause a spectrum of developmental syndromes, further solidifying micronuclei's impact on human health.
Additionally, using CRISPR/Cas9 to screen for genes that affect DSCC1 proliferation, the analysis found that SIRT1, an inhibiting protein, could partially rescue the cell's viability defects induced by DSCC1 loss. This finding suggests that SIRT inhibitors could potentially be developed for the treatment of genetic disorders, such as cohesinopathies.
'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' added Professor Balmus.
The study data has helped to shed light on what determines genetic instability in vivo and provide a conceptual platform for identifying genetic modifications in relation to human disease.
'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,' said Dr David Adams, first author of the study, from the Wellcome Sanger Institute. '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.'
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