PXD045110-3

PXD045110 is an original dataset announced via ProteomeXchange.

Title	Genetic determinants of genomic stability identified by comprehensive in vivo analyses of micronucleus formation
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:14:52.300.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Graeme Benstead-Hume
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-05 08:04:40	ID requested
1	2023-11-17 04:51:46	announced
2	2024-03-18 07:28:03	announced	2024-03-18: Updated project metadata.
⏵ 3	2024-10-22 06:14:53	announced	2024-10-22: Updated project metadata.

10.1038/s41586-023-07009-0;

Adams DJ, Barlas B, McIntyre RE, Salguero I, van der Weyden L, Barros A, Vicente JR, Karimpour N, Haider A, Ranzani M, Turner G, Thompson NA, Harle V, Olvera-Le, ó, n R, Robles-Espinoza CD, Speak AO, Geisler N, Weninger WJ, Geyer SH, Hewinson J, Karp NA, Fu B, Yang F, Kozik Z, Choudhary J, Yu L, van Ruiten MS, Rowland BD, Lelliott CJ, Del Castillo Velasco-Herrera M, Verstraten R, Bruckner L, Henssen AG, Rooimans MA, de Lange J, Mohun TJ, Arends MJ, Kentistou KA, Coelho PA, Zhao Y, Zecchini H, Perry JRB, Jackson SP, Balmus G, Tudor CL, Green AL, Mazzeo CI, Siragher E, Lillistone C, Gleeson D, Sethi D, Bayzetinova T, Burvill J, Habib B, Weavers L, Maswood R, Miklejewska E, Woods M, Grau E, Newman S, Sinclair C, Brown E, Doe B, Galli A, Ramirez-Solis R, Ryder E, Steel K, Bradley A, Skarnes WC, Adams DJ, Lafont D, Vancollie VE, McLaren RSB, Hughes-Hallett L, Rowley C, Sanderson E, Tuck E, Dabrowska M, Griffiths M, Gannon D, Cockle N, Kirton A, Bottomley J, Ingle C, Lelliott C, White JK, Genetic determinants of micronucleus formation in vivo. Nature, 627(8002):130-136(2024) [pubmed]

submitter keyword: genomic stability,micronucleus formation

Jyoti Choudhary
contact affiliation	Functional Proteomic, ICR
contact email	jyoti.choudhary@icr.ac.uk
lab head
Graeme Benstead-Hume
contact affiliation	ICR
contact email	ghume@icr.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/11/PXD045110

PRIDE project URI

• PRIDE
  1. PXD045110
     1. Label: PRIDE project
     2. Name: Genetic determinants of genomic stability identified by comprehensive in vivo analyses of micronucleus formation