Updated project metadata. Genomic instability arising from defective DNA damage response or mitotic chromosomal imbalance can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and genomic instability-associated diseases, the catalogue of genetic players that regulate their generation 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 whose orthologs are linked to human disease. We found that Dscc1 (DNA replication and sister chromatid cohesion 1) null mice, which had the highest number of MN, also displayed a range of phenotypes characteristic of cohesinopathy patients. After validating the DSCC1-MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. Perhaps surprisingly, we found that loss of Sirtuin 1 (SIRT1) can rebalance/rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of SMC3 (structural maintenance of chromosomes protein 3) protein acetylation. Our study reveals a wealth of novel factors involved in maintaining genomic stability and shows how this information can be used to uncover mechanisms relevant to human disease biology.