Genetic determinants of micronucleus formation in vivo

Adams, D. J.; Barlas, B.; McIntyre, R. E.; Salguero, I.; Weyden, L.; 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.; Geisler, N.; Weninger, W. J.; Geyer, S. H.; Hewinson, J.; Karp, N. A.; Fu, B.; Yang, F.; Kozik, Z.; Choudhary, J.; Yu, L.; Ruiten, M. S.; Rowland, B. D.; Lelliott, C. J.; Velasco-Herrera, M. Castillo; Verstraten, R.; Bruckner, L.; Henssen, A. G.; Rooimans, M. A.; Lange, J.; Mohun, T. J.; Arends, M. J.; Kentistou, K. A.; Coelho, P. A.; Zhao, Y.; Zecchini, H.; Perry, J. R. B.; Jackson, S. P.; Balmus, G.

Genetic determinants of micronucleus formation in vivo

D. J. Adams (), B. Barlas, R. E. McIntyre, I. Salguero, L. Weyden, A. Barros, J. R. Vicente, N. Karimpour, A. Haider, M. Ranzani, G. Turner, N. A. Thompson, V. Harle, R. Olvera-León, C. D. Robles-Espinoza, A. O. Speak, N. Geisler, W. J. Weninger, S. H. Geyer, J. Hewinson, N. A. Karp, B. Fu, F. Yang, Z. Kozik, J. Choudhary, L. Yu, M. S. Ruiten, B. D. Rowland, C. J. Lelliott, M. Castillo Velasco-Herrera, R. Verstraten, L. Bruckner, A. G. Henssen, M. A. Rooimans, J. Lange, T. J. Mohun, M. J. Arends, K. A. Kentistou, P. A. Coelho, Y. Zhao, H. Zecchini, J. R. B. Perry, S. P. Jackson and G. Balmus ()
Additional contact information
D. J. Adams: Wellcome Sanger Institute
B. Barlas: University of Cambridge
R. E. McIntyre: Wellcome Sanger Institute
I. Salguero: University of Cambridge
L. Weyden: Wellcome Sanger Institute
A. Barros: Wellcome Sanger Institute
J. R. Vicente: University of Cambridge
N. Karimpour: University of Cambridge
A. Haider: University of Cambridge
M. Ranzani: Wellcome Sanger Institute
G. Turner: Wellcome Sanger Institute
N. A. Thompson: Wellcome Sanger Institute
V. Harle: Wellcome Sanger Institute
R. Olvera-León: Wellcome Sanger Institute
C. D. Robles-Espinoza: Wellcome Sanger Institute
A. O. Speak: Wellcome Sanger Institute
N. Geisler: Wellcome Sanger Institute
W. J. Weninger: Medical University of Vienna
S. H. Geyer: Medical University of Vienna
J. Hewinson: Wellcome Sanger Institute
N. A. Karp: Wellcome Sanger Institute
B. Fu: Wellcome Sanger Institute
F. Yang: Wellcome Sanger Institute
Z. Kozik: The Institute of Cancer Research
J. Choudhary: The Institute of Cancer Research
L. Yu: The Institute of Cancer Research
M. S. Ruiten: The Netherlands Cancer Institute
B. D. Rowland: The Netherlands Cancer Institute
C. J. Lelliott: Wellcome Sanger Institute
M. Castillo Velasco-Herrera: Wellcome Sanger Institute
R. Verstraten: Wellcome Sanger Institute
L. Bruckner: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
A. G. Henssen: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
M. A. Rooimans: Amsterdam UMC, Vrije Universiteit Amsterdam
J. Lange: Amsterdam UMC, Vrije Universiteit Amsterdam
T. J. Mohun: MRC, National Institute for Medical Research
M. J. Arends: Cancer Research UK Scotland Centre, Institute of Genetics & Cancer The University of Edinburgh
K. A. Kentistou: Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine
P. A. Coelho: University of Cambridge
Y. Zhao: University of Cambridge
H. Zecchini: Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine
J. R. B. Perry: Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine
S. P. Jackson: University of Cambridge
G. Balmus: Wellcome Sanger Institute

Nature, 2024, vol. 627, issue 8002, 130-136

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-023-07009-0

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