biostudies-literatureAdams DJCancer Research UKEuropean Research CouncilMedical Research CouncilThe Francis Crick InstituteNHGRI NIH HHSWellcome Trust130-136https://www.ebi.ac.uk/biostudies/studies/S-EPMC10917660biostudies-literatureUnknown627(8002)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.NatureGenetic determinants of micronucleus formation in vivo.PMC1091766018795CRI_CORE_LIMIC_23241879610117319661DRCPGM\100005U54 HG006370206388/Z/17/ZMC_UU_00006/2UKDRI-2006855741MC_UU_12015/2Woods MHewinson JSkarnes WCLelliott CJHughes-Hallett LRyder EKirton ABrown EThompson NALelliott Cde Lange JBottomley JSinclair CCockle NBayzetinova TSalguero IRooimans MAGalli ABurvill JKozik ZDel Castillo Velasco-Herrera MVerstraten RGreen ALMohun TJOlvera-Leon RMcLaren RSBNewman SKentistou KAIngle CBarros ABalmus GMaswood Rvan Ruiten MSWeninger WJZecchini HYang FArends MJVicente JRRobles-Espinoza CDSethi DRamirez-Solis RMcIntyre REDabrowska MHabib BChoudhary JMazzeo CIWeavers LMiklejewska ESanderson ESpeak AOGleeson DSteel KGeisler NYu LGriffiths MKarimpour NGeyer SHZhao YDoe BCoelho PATurner GTudor CLAdams DJBruckner LHarle VSiragher EHenssen AGTuck EGannon DRowland BDBarlas BPerry JRBBradley AJackson SPRanzani MHaider AKarp NAvan der Weyden LRowley CFu BLillistone CWhite JKSanger Mouse Genetics ProjectGrau ELafont DVancollie VEfalseGenetic determinants of micronucleus formation in vivo.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 biology¹.2024-01-01T00:00:00Z2024 Mar2026-06-09T07:08:36.184Z2025-04-07T02:12:40.437ZS-EPMC109176603835579310.1038/s41586-023-07009-0