Genetic determinants of genomic stability identified by comprehensive in vivo analyses of micronucleus formation

ABSTRACT: Genomic instability due to defective DNA damage response or arising from mitotic chromosomal imbalance can lead to sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of genomic instability associated diseases and ageing, the catalogue of genetic players that regulate their generation remains to be determined. Here analysed 996 mouse mutant lines, revealing 143 factors whose loss significantly increases (71) or decreases (72) MN formation. Most such genes, including the Dscc1 (DNA replication and sister chromatid cohesion 1) gene, have never been studied in mouse models. We found that Dscc1 defective mice were sub-viable and displayed phenotypes like the clinical characteristics of cohesinopathy patients. After validating the DSCC1-MN phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define its synthetic lethal and synthetic viable 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 provides a resource of novel factors involved in maintenance of genomic stability and shows how this information can be used to uncover mechanisms relevant to better understand disease biology.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: James Wright  

LAB HEAD: Prof. Jyoti Choudhary

PROVIDER: PXD030499 | Pride | 2023-11-17

REPOSITORIES: Pride