PXD030499-1

PXD030499 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 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.
HostingRepository	PRIDE
AnnounceDate	2023-11-17
AnnouncementXML	Submission_2023-11-17_03:07:55.985.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	James Wright
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-17 13:31:04	ID requested
⏵ 1	2023-11-17 03:07:56	announced
2	2024-03-18 07:27:54	announced	2024-03-18: Updated project metadata.
3	2024-10-22 06:14:47	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: MS3, Human,TMT

Prof. Jyoti Choudhary
contact affiliation	The Institute of Cancer Research
contact email	jyoti.choudhary@icr.ac.uk
lab head
James Wright
contact affiliation	The Institute of Cancer Research
contact email	james.wright@icr.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030499
     1. Label: PRIDE project
     2. Name: Genetic determinants of genomic stability identified by comprehensive in vivo analyses of micronucleus formation