Genetic determinants of micronucleus formation in vivo
Author:
Adams D. J.ORCID, Barlas B., McIntyre R. E., Salguero I., van der Weyden L.ORCID, Barros A., Vicente J. R., Karimpour N., Haider A., Ranzani M., Turner G., Thompson N. A., Harle V., Olvera-León R., Robles-Espinoza C. D., Speak A. O.ORCID, Geisler N., Weninger W. J., Geyer S. H.ORCID, Hewinson J., Karp N. A., , Tudor Catherine L., Green Angela L., Mazzeo Cecilia Icoresi, Siragher Emma, Lillistone Charlotte, Gleeson Diane, Sethi Debarati, Bayzetinova Tanya, Burvill Jonathan, Habib Bishoy, Weavers Lauren, Maswood Ryea, Miklejewska Evelina, Woods Michael, Grau Evelyn, Newman Stuart, Sinclair Caroline, Brown Ellen, Doe Brendan, Galli Antonella, Ramirez-Solis Ramiro, Ryder Edward, Steel Karen, Bradley Allan, Skarnes William C., Adams David J., Lafont David, Vancollie Valerie E., McLaren Robbie S. B., Hughes-Hallett Lena, Rowley Christine, Sanderson Emma, Tuck Elizabeth, Dabrowska Monika, Griffiths Mark, Gannon David, Cockle Nicola, Kirton Andrea, Bottomley Joanna, Ingle Catherine, Lelliott Chris, White Jacqueline K., Fu B., Yang F., Kozik Z., Choudhary J.ORCID, Yu L.ORCID, van Ruiten M. S., Rowland B. D.ORCID, Lelliott C. J., del Castillo Velasco-Herrera M.ORCID, Verstraten R., Bruckner L., Henssen A. G.ORCID, Rooimans M. A., de Lange J., Mohun T. J., Arends M. J.ORCID, Kentistou K. A., Coelho P. A., Zhao Y., Zecchini H., Perry J. R. B.ORCID, Jackson S. P.ORCID, Balmus G.ORCID
Abstract
AbstractGenomic 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.
Publisher
Springer Science and Business Media LLC
Reference90 articles.
1. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009). 2. Leibowitz, M. L., Zhang, C.-Z. & Pellman, D. Chromothripsis: a new mechanism for rapid karyotype evolution. Annu. Rev. Genet. 49, 183–211 (2015). 3. Campbell, P. J. et al. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020). 4. Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017). 5. Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).
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