PXD009650-2

PXD009650 is an original dataset announced via ProteomeXchange.

Title	53BP1 cooperation with the REV7–shieldin complex underpins DNA structure-specific NHEJ
Description	53BP1 governs a specialized, context-specific branch of the classical non-homologous end joining DNA double-strand break repair pathway. Mice lacking 53bp1 (also known as Trp53bp1) are immunodeficient owing to a complete loss of immunoglobulin class-switch recombination, and reduced fidelity of long-range V(D)J recombination. The 53BP1-dependent pathway is also responsible for pathological joining events at dysfunctional telomeres, and its unrestricted activity in Brca1-deficient cellular and tumour models causes genomic instability and oncogenesis. Cells that lack core non-homologous end joining proteins are profoundly radiosensitive, unlike 53BP1-deficient cells, which suggests that 53BP1 and its co-factors act on specific DNA substrates. Here we show that 53BP1 cooperates with its downstream effector protein REV7 to promote non-homologous end joining during class-switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. We identify shieldin—a four-subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2) and FLJ26957 (SHLD3)— as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and non-homologous end joining during class-switch recombination, and supports toxic non-homologous end joining in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the context specificity of the pathway.
HostingRepository	PRIDE
AnnounceDate	2018-07-26
AnnouncementXML	Submission_2018-07-26_08:25:27.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD009650
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Roman Fischer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	Ethyl; Ammonia-loss; Cation:Fe[II]; Amidated; Methyl; Oxidation; Methylphosphonate; Ethanolyl; Carboxy; CAMthiopropanoyl; Decanoyl; Propionamide; Phospho; GlycerylPE; Cation:Zn[II]; Didehydro; Cation:Na; Deamidated; Trp->Kynurenin; Acetyl; GlyGly; Malonyl; Delta:S(-1)Se(1); Formyl; Carbamyl; Carbamidomethyl; Cation:Ca[II]; Gln->pyro-Glu; Guanidinyl; Dehydrated; Dioxidation; Hydroxymethyl; MercaptoEthanol
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2018-05-02 10:42:40	ID requested
1	2018-07-26 08:17:54	announced
⏵ 2	2018-07-26 08:25:28	announced	Updated publication reference for DOI(s): 10.1038/s41586-018-0362-1s41586-018-0362-1.
3	2018-07-27 08:40:09	announced	Updated publication reference for DOI(s): 10.1038/s41586-018-0362-1s41586-018-0362-1.
4	2024-10-22 04:44:58	announced	2024-10-22: Updated project metadata.

s41586-018-0362-1;

10.1038/s41586-018-0362-1;

curator keyword: Biological

submitter keyword: REV7 Shieldin

Roman Fischer
contact affiliation	Target Discovery Institute, University of Oxford
contact email	roman.fischer@ndm.ox.ac.uk
lab head
Roman Fischer
contact affiliation	University of Oxford
contact email	roman.fischer@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD009650
     1. Label: PRIDE project
     2. Name: 53BP1 cooperation with the REV7–shieldin complex underpins DNA structure-specific NHEJ