Genetic determinants of micronucleus formation in vivo

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 Tudor, Catherine L. and Green, Angela L. and Mazzeo, Cecilia Icoresi and Siragher, Emma and Lillistone, Charlotte and Gleeson, Diane and Sethi, Debarati and Bayzetinova, Tanya and Burvill, Jonathan and Habib, Bishoy and Weavers, Lauren and Maswood, Ryea and Miklejewska, Evelina and Woods, Michael and Grau, Evelyn and Newman, Stuart and Sinclair, Caroline and Brown, Ellen and Doe, Brendan and Galli, Antonella and Ramirez-Solis, Ramiro and Ryder, Edward and Steel, Karen and Bradley, Allan and Skarnes, William C. and Adams, David J. and Lafont, David and Vancollie, Valerie E. and McLaren, Robbie S. B. and Hughes-Hallett, Lena and Rowley, Christine and Sanderson, Emma and Tuck, Elizabeth and Dabrowska, Monika and Griffiths, Mark and Gannon, David and Cockle, Nicola and Kirton, Andrea and Bottomley, Joanna and Ingle, Catherine and Lelliott, Chris and White, Jacqueline K. 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. (2024) Genetic determinants of micronucleus formation in vivo. Nature. ISSN 0028-0836

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Abstract

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 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 biology1.

Item Type: Article
Subjects: Pustaka Library > Multidisciplinary
Depositing User: Unnamed user with email support@pustakalibrary.com
Date Deposited: 21 Feb 2024 06:31
Last Modified: 21 Feb 2024 06:31
URI: http://archive.bionaturalists.in/id/eprint/2265

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