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Genetic determinants of micronucleus formation in vivo

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Item Type:Article
Title:Genetic determinants of micronucleus formation in vivo
Creators Name:Adams, D.J. and Barlas, B. and McIntyre, R.E. and Salguero, I. and van der Weyden, L. and Barros, A. and Vicente, J.R. and Karimpour, N. and Haider, A. and Ranzani, M. and Turner, G. and Thompson, N.A. and Harle, V. and Olvera-León, R. and Robles-Espinoza, C.D. and Speak, A.O. and Geisler, N. and Weninger, W.J. and Geyer, S.H. and Hewinson, J. and Karp, N.A. and Fu, B. and Yang, F. and Kozik, Z. and Choudhary, J. and Yu, L. and van Ruiten, M.S. and Rowland, B.D. and Lelliott, C.J. and Del Castillo Velasco-Herrera, M. and Verstraten, R. and Bruckner, L. and Henssen, A.G. and Rooimans, M.A. and de Lange, J. and Mohun, T.J. and Arends, M.J. and Kentistou, K.A. and Coelho, P.A. and Zhao, Y. and Zecchini, H. and Perry, J.R.B. and Jackson, S.P. and Balmus, G.
Abstract: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). Although MN are a hallmark of ageing 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. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology.
Keywords:Cancer Genetics, DNA Damage and Repair, Genomic Instability, High-Throughput Screening, Animals, Mice
Publisher:Nature Publishing Group
Page Range:130–136
Date:7 March 2024
Official Publication:https://doi.org/10.1038/s41586-023-07009-0
PubMed:View item in PubMed

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